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https://f1000research.com/articles/9-89/v1
|
07 Feb 20
|
{
"type": "Brief Report",
"title": "Use of the K factor from the Universal Soil Loss Equation can show arable land in Palau",
"authors": [
"Masato Oda",
"Yin Yin Nwe",
"Hide Omae",
"Yin Yin Nwe",
"Hide Omae"
],
"abstract": "Palau is an island in the Micronesia region of the western Pacific Ocean. The island receives heavy rainfall and has steep slopes, so 92% of the land is categorized within the most erodible rank, with a T factor of 5. A recent study reported that the water infiltration rate is proportional to the root mass of the crop soil; therefore, we attempted to evaluate the performance of root mass for preventing soil erosion. We covered parts of the land, with a slope of 15.4° (13.4°–17.3°), with weed control fabric to prevent the growth of grass and roots, then removed the fabric, cultivated the land, planted sweet potatoes, and compared the amount of soil erosion with other areas. Surprisingly, there was no erosion at all in the test plots, although there were 24 rainfall events that caused erosion. For the parameters of the Universal Soil Loss Equation (USLE) equation used in the present study, only the K factor was not actually measured. This means the K factor was larger than the actual value. Land at low risk of soil erosion and suitable for agriculture can be found by measuring K factor locally, even if the area is categorized as unsuitable.",
"keywords": [
"Babeldaob",
"hillside farming",
"island",
"tillage",
"mulching",
"USLE equation"
],
"content": "Introduction\n\nPalau forms part of the Micronesia region in the western Pacific Ocean. There are open agricultural fields that were once utilized by the Japanese, prior to World War Two. The redevelopment of these fields is starting to occur. Generally, fields with inclines of more than 8° are unsuitable for growing crops, but most of the agricultural fields in Palau have slopes of more than 8°. As well as having steep slopes, the island is also subject to heavy rainfall, therefore 92% of the land is categorized within the most erodible rank, having a T factor of 5 (more than 5 tons per acre per year) (Smith, 1983). In recent studies, the estimated risk of soil erosion from agricultural land was reported to be from 720 to 813 tons per ha per year (USDA Natural Resources Conservation Service, 2003). No-tillage farming is effective for preventing soil erosion (Zuazo & Pleguezuelo 2009), but the use of herbicides is unfavorable in Palau from an ecological perspective. Therefore, either tillage or the use of weed control fabric is necessary. The problem of tillage is the early stage of the crop of small vegetation coverage (Wischmeier & Smith 1978). It is essential to increase the water infiltration rate at this stage. The water infiltration rate is positively proportional to the root mass of the crop soil (Oda et al., 2019). Here, we clarified the risk of erosion in a field with an incline typical for Palau. In addition, we clarified the aftereffects of using weed control fabric, because the use of these fabrics can reduce root mass in the tropics and may result in erosion (Oda et al., 2019).\n\n\nMethods\n\nThe experiment was conducted at the Palau Community College Research and Development Station (N7.53, E134.56). The soil here comprises “Ngardmau-Bablethuap Complex”, which is characterized as a very gravelly loam with low organic matter content of between 1% and 4% (Smith, 1983). The T factor is more than 5 tons per acre per year, although the permeability is moderately rapid (15–50 cm/hr) and very well drained. The available water capacity is between 0.05 and 0.10 cm/cm (Smith, 1983). The previous crop grown on the land was taro (Colocasia esculenta). The slope is 15.4° (13.4°–17.3°).\n\nWe conducted the experiment from January to July 2019. The treatments were plants (with or without) × ridge (with or without) × 2 replications. We set these eight plots (2 × 10 m) randomly on the field (Table 1, Figure 1 and Figure 2). We tilled the field using a hand tractor on 22 January, leveled the field, and covered half the plots with weed control fabric (polypropylene, 0.4-mm thick, 120 g m–2; I-Agri Corp., Tsuchiura) on 28 January. We cut weeds on 16 April, blew off the residue, removed the weed control fabric on 17 April (Figure 3), then tilled each plot using the hand tractor up and down so that the soil did not mix. The average thickness of the soil tilled was 16 cm. We made a 70 cm width of the monitoring areas in the center of the plots by ridges or wooden boards (for the no-ridge treatment). We transplanted sweet potatoes (Ipomoea batatas) at 70 cm intervals on 17 April (Figure 4). We dug trenches at the upper end of the fields to prevent rainwater inflow. We embanked the lower ends and added 1-m lengths of weed control fabric to trap any eroded soil. Fertilizer was not applied. Hand weeding was conducted on 21 May and 6 June.\n\nGreen: No mulch treatment, Stripe: Ridge treatment.\n\nThe order of the plots is 4, 7, 1, 5, 6, 8, 2, 3.\n\nFollowing every heavy rainfall event, we collected any soil that had been eroded. We collected precipitation data every 5 minutes via a weather station in the Palau Community College Research and Development Station. The condition of the fields was recorded using an automatic camera.\n\nWe identified rainfall events that caused severe erosion (more than 3 mm/10 min) (Onaga, 1969) and compared the amount of eroded soil of each events.\n\nWe estimated erosion using the Universal Soil Loss Equation (USLE) equation (Wischmeier & Smith 1978).\n\nA = R×K×LS×P×C metric ton ha–1 year–1\n\nE=210+89 log10 I30 100 metric ton ha–1\n\nI30 cm h–1: maximum rainfall in 30 min multiplied to 60 min; rainfall less than 1.27 cm is omitted, and the maximum value is 7.62 cm.\n\nA = EI×K×LS×P×C metric ton ha–1\n\nK = 0.15\n\nLS = (10/20.0)^0.5 × (68.19 sin2 15.4° + 4.75sin 15.4°+0.068)= 4.34\n\nP = 1.00; vertical ridge\n\nC =1.0; Tillage\n\nEI = (E×I30)/100\n\nPlot area = 7 m2\n\n\nResults\n\nThe field site received regular rainfall, with total precipitation of 992 mm during the experimental period, from 17 April to 15 July (Figure 5). There were 46 days of erosive rainfall more than 3 mm per 10 min (Figure 6). The rainfall threshold where surface runoff occurs is 2–3 mm per 10 min on a 15° slope, although these values vary according to different soil characteristics (Onaga, 1969). There was a highly erosive rainfall event on day 7 after planting (2 May). Following weeding, an erosive period, a heavy rainfall event of 17 mm per 10 min occurred on the next day after weeding took place. The second weeding was conducted after seven days of intensive rainfall, with a further erosive rainfall event of 7 mm per 10 min that occurred just after weeding took place. Thus, the rainfall conditions during the experimental period were expected to result in severe soil erosion.\n\nThe blocks show a rainfall event of more than 3 mm/10 min and the amount of precipitation. The colors distinguish the events.\n\nThere were 24 rainfall events that could have caused erosion during the observation period (Table 2). The estimated erosion was 0.57 kg of erosion per plot on day 7, the first rainfall event, after transplanting. That was 2.82 kg after first weeding.\n\nDespite the severe rainfall conditions, none of the plots had any erosion at all through the experimental period (Figure 7).\n\nThe estimated erosion was 0.57 kg per plot.\n\nMost of the soil surface was bare by day 14 (1 May). The surface of the soil was covered by small weeds on day 21 (8 May), the day of the first weeding. The vegetation coverage by visual inspection ranged from 15–85% on day 54 (10 Jun), after the second weeding. The vegetation coverage was 100% by day 89 (15 July) (Figure 8).\n\nTop panel: day 14, Upper middle panel: day 21 (before the first weeding), Lower middle panel: day 54 (after second weeding), Bottom panel day 89.\n\n\nDiscussion and conclusion\n\nThe experiment was conducted under severe conditions, with a slope of approximately 15° and vertical ridge. The treatment with weed control fabric was expected to erase the effect of root mass for preventing soil erosion. There were many intensive rainfall events during the experimental period. Nevertheless, no soil erosion occurred. This means that the risk of soil erosion was low for the experimental soil in fields with slopes of less than 15°. Tillage is available. Although the use of mulching material may erase the effect of root mass for preventing soil erosion, still the use of mulching material is available.\n\nThe results were unexpected. The vertical ridge may affect the result because a vertical ridge without a catch canal is less erosive (Shima et al., 1991).\n\nFor the parameters of the USLE equation in the present study, only the K factor was not actually measured. This means that the K factor was larger than the actual value. Low erosion land for agriculture can be found by measuring erosion locally, even if the area is categorized as being unsuitable for field crops. The risk of erosion should be clarified for other soil types, and the effect of the previous crop type too. For taro, the previous crop in these fields, the roots might be left in the soil; although, we took a fallow period. Land suitable for agriculture and at low risk of soil erosion can be found in Palau by determining site-specific K factor measurements.\n\n\nData availability\n\nFigshare: Precipitation of Palau, https://doi.org/10.6084/m9.figshare.11769909.v1 (Oda et al., 2020). Data are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nOda M, Rasyid B, Omae H: Root mass may affect soil water infiltration more strongly than the incorporated residue [version 2; peer review: 1 approved with reservations]. F1000Res. 2019; 7: 1523. Publisher Full Text\n\nOda M, Omae H, Nwe YY: Precipitation of Palau. figshare. Dataset. 2020. https://doi.org/10.6084/m9.figshare.11769909.v1\n\nOnaga K: On the properties of rainfall influenced on soil erosion (Fundamental studies on farmland conservation in okinawa I.). The Science Bulletin of the Faculty of Agriculture. University of the Ryukyus. 1969; 16: 180–187.\n\nShima E, Yamaji E, Koide S, et al.: Effects of Ridge and Catch Canal on Soil Erosion in a Sloping Reclaimed Field of Decomposed Granite Soil. JSIDRE. 1991; 1988(138): 75–82. Reference Source\n\nSmith CW: Soil survey of Islands of Palau Republic of Palau.1983; Washington, DC: USDA. Reference Source\n\nUSDA Natural Resources Conservation Service. Capacity Building with Watershed Communities. 2003.\n\nWischmeier WH, Smith DD: Predicting rainfall erosion losses - a guide to conservation planning. Predicting rainfall erosion losses - a guide to conservation planning. 1978; [Accessed: 19 June 2018]. Reference Source\n\nZuazo VHD, Pleguezuelo CRR: Soil-Erosion and Runoff Prevention by Plant Covers: A Review. In: Lichtfouse, E., Navarrete, M., Debaeke, P., Véronique, S., and Alberola, C. eds. Sustainable Agriculture. Dordrecht: Springer Netherlands. 2009; 785–811. Publisher Full Text"
}
|
[
{
"id": "61753",
"date": "30 Apr 2020",
"name": "Kathleen B. Boomer",
"expertise": [
"Reviewer Expertise Hydrology",
"soil biogeochemistry",
"and watershed 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\nTechnical Review: Use of the K factor from the Universal Soil Loss Equation can show arable land in Palau by Oda et al.\n\nGeneral Comments:\nThe investigators report the results of measured and estimated soil erosion in the Micronesia region of the western Pacific Ocean. To compare how plantings and micro-tilling affects soil detachment and transport to field edges, they established eight plots within a single field, following as closely as possible (presumably) the original protocol of the USLE. Although the title indicates a focus on soil erodibility (K), the study design is more relevant to understanding practice effects on erosion. Given the importance of subsistence agriculture and the lack of studies specific to promoting sustainable practices in this region, this work calls attention to a critical information gap.\nThe manuscript requires extensive revisions to clarify and substantiate its contributions. It lacks a “story arc” that enables the reader to readily understand why this work is important, how the researchers tackled this knowledge gap, and how their results compare or contribute to the existing body of research. For example, the authors might consider highlighting the importance of subsistence farming to the region and the challenge of soil erosion to sustainable agriculture, but the lack of technical guidance specific to the region. The USLE, which is based on a phenomenal US dataset, is a widely accepted tool to evaluate erosion potential based on landscape setting and management, but the empirical model ideally requires local testing and refinements for application to areas outside of its original US study area. The research objectives and methods also require clarification. Finally, the limited number of plots (8) and fields (1) raises concerns about the power of the study to detect differences among field practices. Given the difficulty and expense of field studies and the realities of scant data, however, the publication may be valuable.\n\nSpecific Comments:\nA large portion of the introduction includes study site information, which should go in the Methods section.\n\nUse the international the international system for classification of soils to describe site conditions.\n\nDefine “T factor”.\n\nIn the site description, add information about the landscape setting, outside of the study site boundaries. A study site topographic map would be helpful. Information about the distribution of croplands on the study island, as well as a brief description of how the island compares to others in the region, would be helpful to thinking about the value of information beyond the study site.\n\nIn the methods section, add a paragraph describing how and where rainfall data were collected. Include this location on the study area map.\n\nIt is not clear how tilling, even if by hand, does not mix soils.\n\nElaborate on how soil erosion was measured. Reference methods to the extent possible.\n\nElaborate on USLE application and parameterization. Use previous publications as examples.\n\nIn the “Estimated erosion” section, define “That” in the last sentence on page 3.\n\nConsolidate Figure 6 into one panel.\n\nIn the Discussion and Conclusions section, paragraph 1, reference to site conditions seem contradictory: “experiment was under sever conditions, with a slope of … 15°” vs “risk of soil erosion was low for the experimental soil”.\n\nConvert Table 2 to graphical form. For example, plot A vs EI, observed vs predicted, grouped by practice.\n\nThe pictures are difficult to interpret.\n\nThe discussion needs to follow the same “story arc” presented in the introduction and used to organize the methods and results sections.The discussion also needs to compare the study results with the existing body of literature to assess whether findings to reinforce or challenge existing paradigms.The authors also need to acknowledge the limitations of their study design and ideally, discuss the relevance of their findings to management recommendations.\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? No\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": "5545",
"date": "26 May 2020",
"name": "Masato Oda",
"role": "Author Response",
"response": "Thank you for the constructive comments.We will accept almost of all the comments; however, before submitting a revised manuscript, may I clarify the following points?1) Consolidate Figure 6 into one panel.Is that mean combine Figure 6 and Figure 5?2) Convert Table 2 to graphical form. For example, plot A vs EI, observed vs predicted, grouped by practice. This is less effective because the practical data were all zero."
},
{
"c_id": "5570",
"date": "02 Jun 2020",
"name": "Masato Oda",
"role": "Author Response",
"response": "Define “T factor”. Now, I understood that I misunderstood the meaning of the \"T factor\". Thank you so much."
},
{
"c_id": "5637",
"date": "24 Jun 2020",
"name": "Masato Oda",
"role": "Author Response",
"response": "Clarified the “story arc” of the paper including the lack of technical guidance specific to the region, the research objectives, and methods. The description of Palau was moved to the Methods section. The international classification of soils was added. Define of the “T factor” was corrected. A Google map link was added as an alternative of the topographic map The information on the experimental field was added. The distance of the weather station was added. The link of a picture of the hand tractor is added. The method of collecting eroded soil was clarified more. The application and parameterization of USLE were clarified more. “That” in the last sentence on page 3 was clarified. We couldn’t understand the meaning of “Consolidate Figure 6 into one panel”. We improved the readability. The first paragraph pointed out a contradiction and interpreted that in the second and the third paragraph. No erosion was observed so the changing Table 2 to graphical form is ineffective. We corrected estimated → predicted, actual was zero. The discussion section was improved."
}
]
}
] | 1
|
https://f1000research.com/articles/9-89
|
https://f1000research.com/articles/10-429/v1
|
28 May 21
|
{
"type": "Brief Report",
"title": "Global stability analysis of hepatitis B virus dynamics",
"authors": [
"Olajumoke Oludoun",
"Olukayode Adebimpe",
"James Ndako",
"Oluwakemi E. Abiodun",
"Babatunde Gbadamosi",
"Benedicta B. Aladeitan",
"Olukayode Adebimpe",
"James Ndako",
"Oluwakemi E. Abiodun",
"Babatunde Gbadamosi",
"Benedicta B. Aladeitan"
],
"abstract": "This paper considers the impact of an acute individual's spontaneous clearance, recovery of a chronic individual with full immunity, and risk factor reduction on a hepatitis B virus (HBV) model. The existence and the positivity solution of the model are established. The model threshold quantity is defined and sensitivity analysis is analyzed to demonstrate the effect of various parameters on the spread of the virus. The global stability analysis of the equilibrium is shown using Lyapunov and comparison theorem methods. Finally, computational simulation is presented to validate the analytical solution. The results show that treatment, spontaneous clearance and reduction of the risk factor are highly successful in transmitting and regulating HBV transmission. The effective measure of these parameters as substantiated by our simulations, providing an excellent control method of the transmissible infection of HBV.",
"keywords": [
"Hepatitis B",
"mathematical model",
"positivity and existence",
"global stability",
"sensitivity",
"Lyapunov method",
"simulation"
],
"content": "Introduction\n\nHepatitis B is a common liver infection caused by the potentially life-threatening hepatitis B virus (HBV). HBV can cause a serious infection, which places individuals at high risk of dying from fibrosis and cirrhosis of liver. It is a huge worldwide health issue. As reporting by the World Health Organization, around 360 million of the 2 billion people infected with the HBV are reported to have a lifelong chronic infection, and 887,000 of those individuals die from liver cirrhosis or primary hepatocellular carcinoma (WHO, 2020). As of 2016, 27 million individuals (10.5%) of all people considered to be living with HBV were aware of their infection, while 4.5 million (16.7%) of those diagnosed were receiving treatment (WHO, 2019). The Western Pacific region recorded the highest incidence rate of HBV at 6.2% of the adult population, while this was 6.1% in the African region, and 0.7% in the American region on (WHO, 2019). Although HBV lives outside the body for about seven days, it is still very possible for it to cause an infection if it is injected into an unvaccinated individual. It takes about 75 days on the average for the HBV to incubate but this can vary between 30 and 180 days. Detection of the virus can be between 30 and 60 days of being infected or consequently mature into full-blown HBV (CDC, 2019).\n\nThe HBV, a hepatotropic non-cytopathic virus, is responsible for the disease (Ribiero, 2002). In highly endemic areas, perinatal transmission or horizontal transmission (exposure to infected blood) are the primary means of transmission (Pan and Zhang, 2005). The most common method of transmission is from mother to child at birth, particularly from infected children to uninfected children within the first 5 years of life. Contaminated body fluids such as vaginal discharge, saliva, menstrual flow, and semen are other means of transmission (Pan and Zhang, 2005). Rarer means of transmission include transpiration, breast milk, sweat, and urine by percutaneous or mucosal exposure of infected individuals (Mpeshe and Nyerere, 2019). In particular, unvaccinated men who have sex with men and heterosexual people with several sexual partners or who have contact with sex workers may experience sexual transmission of HBV (Khan et. al, 2019). In less than 5% of cases, infections lead to chronic hepatitis in adulthood. Virus transmission can also occur either in health care facilities or through the reuse of needles and syringes among individuals who inject drugs. Furthermore, infection can occur during medical, surgical and dental procedures, by tattooing, or by using razors and similar products contaminated with infected blood (Mpeshe and Nyerere, 2019).\n\nTypically, there is a 5-10% chance of recovery for adults that develop chronic infections (Chenar et al., 2018). Host variables are believed to be responsible for determining whether the infection is cleared or becomes chronic, especially immune responses (Ciupe et al., 2007). Different aspects of HBV dynamics and the immune response during infection have been investigated by several mathematical models (Ribiero, 2002; Long et al., 2008; Lau et al., 2009; Wang et al., 2010; Qesmi et al., 2010; Pang et al., 2010).\n\nAs a result of the research mentioned above, we present an infectious disease model to better understand how testing and treatment affects HBV transmission dynamics and prevalence. The model formulation of HBV transmission dynamics, as well as the dynamical behavior of the model, including equilibria and stabilities is presented in this paper. The aim of this study is to contribute to the development of HBV control strategies and the establishment of intermediate objectives for intervention programs.\n\n\nModel formulation\n\nIt has been clinically shown that a proportion of HBV acutely infected individuals can spontaneously clear the virus (Pan and Zhang, 2005). Also, infectious individuals under treatment can become prone to re-infection if they discontinue treatment, or consume alcohol or use of drugs, which can reduce the impact of the treatment. In view of this, the following model is developed where the population is divided into different states, namely: the susceptible, the acute, the chronic carriers, the treated and the recovered states.\n\nAt timet, denoted by Nt, the total population is divided into the following five classes/subgroups (Table 1) corresponding to different epidemiological status.\n\nwhere St are the susceptible populace, At is the populace that are acutely infected with HBV, Ct are the chronically/clinically infected individuals, while Tt are individuals under treatment and Rt are the recovered classes.\n\nFigure 1 schematically represents the epidemiology of HBV. The various disease stages are replicated by the various compartments (circle) and the arrows demonstrate the way an individual progress from one state to the other. It is assumed that at time t, susceptible individual S, enter the population at a constant rateζ1−α1−γC where ζis the birth rate,α is the proportion of population successfully immunized, while γis the probability that children born to carrier mothers will develop to chronic state. For all classes, individuals die at a constant natural mortality rate, μ. We assume that HBV infected individuals on treatment are infectious. Susceptible individual S may acquire HBV infection when in contact with individuals in A,C,andT populace at a rate λs (force of infection associated with HBV), where\n\nwhere βAand βC are the effective contact rate for HBV infection to occur/probability that a contact will result in an Acute and Chronic HBV compartment, respectively. Modification ξ>1 accounts for a higher risk of HBV acquisition for people living with Chronic HBV.\n\nA proportion of the acute HBV infected individuals η, becomes chronic carriers and then get treated at σ, while the remaining proportion 1−η spontaneously clear the virus. 1ω is the duration of acute phase. A proportion of the treated HBV individuals, κ, recover with full immunity, some were in the process of recovering in the treated populace at a rate, υ and duration for the treatment is given as ρ while the remaining proportion 1−κ becomes susceptible. Those individuals in the process of recovering in the treated populace at a rate, υ if engaging/exposed to high-risk habit and those on treatment ρ can be re-infected at the rate νρ if they discontinue treatment at a rate of ε.\n\nwhere λs=βA+ξ1βC+ξ2βT\n\n\nModel implementation\n\nFrom model (3), we observed that the variables are nonnegative and the solutions are non-negative for all time t≥0. The parameters used are assumed to be positive and show that the feasible solutions are bounded in the region.\n\nLemma 1: The initial values of the parameters are\n\nThen the solution of the model StAtCtTtRtNt is positive for all t≥0.\n\nProof: Considering the first equation in (3),\n\nwe have,\n\nHence, S≥0\n\nWith respect to the second equation in (3), we have\n\nHence, A≥0\n\nThe same approach applies to the proof of the positivity of C, T and R.\n\nThe disease-free equilibrium of the model (3) exists and is given by:\n\nThe endemic steady state of the model (3) exists and is presented as follows:\n\nwhere\n\nBy using the next generation matrix, the basic reproduction number is determined and given by:\n\nThe reproduction number is given by ρ(FV−1), and\n\nThe global stability of the disease-free equilibrium was investigated using the Comparison method at the disease - free equilibrium Eo. Theorem 1 proves the global stability of disease -free equilibrium Eo\n\nTheorem 1: The disease - free equilibrium Eo of system (3) is globally asymptotically stable if Ro<1 and unstable if Ro>1.\n\nProof: The Comparison method as implemented in Lashmkantham, et al (1989) and Mushayabasa et al (2011) is used here. The rate of change of the acute and chronic components of system (3) can be written as\n\nwhere,\n\nSince at the disease free A=C=T=R=0→0000 and S≤Nas t→∞.\n\nThus,\n\nThen all eigenvalues of the matrix F−V have negative real parts, i.e\n\nEquation (11) has three negative roots by Descartes rule of signs if\n\nIt follows that the linearized differential inequality is stable whenever R0<1. Consequently, ACT→000 as t→∞. Evaluating system (3) at A=C=T=0 gives S→1for R0<1. Hence, the disease-free equilibrium E0 of system (3) is globally asymptotically stable if R0<1. The result also follows immediately that the disease-free equilibrium E0 of system (3) is unstable if R0>1.\n\nTheorem 2: The equations of the model has a positive distinctive endemic equilibrium whenever R0 > 1, which is said to be globally asymptotically stable.\n\nProof: Considering the Lyapunov function defined as:\n\nwhere L takes it derivative along the system directly as:\n\nAt equilibrium,\n\nwhere,\n\nP1≤0 whenever\n\nandP2≤0 whenever\n\nThus,\n\ndLdt≤0 if the condition in (19) and (20) holds.\n\nTherefore, by LaSalle asymptotic stability theorem (LaSalle, 1976), and Adeniyi et al. (2020), the positive equilibrium state dLdt is globally asymptotically stable in the positive region R+5.\n\nTo test the strength of the model and the parameter values, a sensitivity study was carried out. This is done in order know the parameters that have a huge influence on the basic reproduction number (R0) which is done using Maple 19 software. A variable k; a normalized forward sensitivity index which depends on a parameter: ℓ differentially, is defined as:\n\nThe R0 sensitivity is therefore derived from each of the different parameters listed in Table 1. All expressions are complex for sensitivity indices, so sensitivity indices are evaluated in Table 2 at the baseline parameter values.\n\n\nModel validation\n\nTo validate our analytical results, we perform numerical simulations of the proposed model (2). These simulations are based on qualitative analysis. Some of the parameters were obtained from published research, while others were estimated by the authors as they were thought to be biologically feasible. We employ a strictly numerical RK (Runge-Kutta) technique of order four embedded in the Maple 19 software. Table 3 contains the parameter's comprehensive values.\n\nConsidering the first sizes of compartmental population, taking the parameter values and the interval (0-60) using the linear stability analysis, we perform the simulations and obtain the outcomes shown in Figure 2. The dynamic behavior of susceptible individuals is represented in Figure 2A, showing the existence of the susceptible individuals. It was discovered from Figure 2B that the acute populace decreases with the passage of time. Ditto the behaviors of chronic, treated and recovered populace, respectively, are dynamically represented in Figure 2C, D and E. The trajectories S(t), A(t), C(t), T(t), and R(t) distinctly converge to the disease-free equilibrium of E0 = (S_0, 0, 0, 0, 0, R_0) = (1.678018396, 0, 0, 0, 0, 0, 0, 0.06801334973) as indicated in Eq. (10), when R0 = 0.07150316516< 1. The dynamics of the susceptible populace with respect to the treatment rate σ, recovering rate with full immunity k and the rate at which recovered individual fallout from risk reduction ϵ is shown in Figure 3A. It is evident from Figure 3A that with the increase in the parametric values, the susceptible population increases, even as increase is not evident due to those who recover with complete immunity. However, there is still an increase due to some people who fall out of risk reduction, checking the cumulative impact of the parameters causing the increment of the susceptible populations. The inverse relationship of the compartmental population (acute and chronic) with the variance of the above parameters is shown in Figure 3B and C. This means that it is possible to minimize acute and chronic individuals by increasing the parametric values. The variation of the treated and recovered populace is shown in Figure 3D and E. An increase in the treated and the recovered population is caused by increasing the values of the parameters. It can be clearly inferred from our computational simulations that treatment, spontaneous clearance and reduction of the risk factor are highly successful in transmitting and regulating HBV transmission. The effective measure of these parameters as substantiated by the simulations is an excellent control method of the transmissible infection of HBV.\n\n\nConclusion\n\nA deterministic model of hepatitis B that involves the spontaneous clearance of an acute individual and also recovery of chronic individual with full immunity and risk factor reduction was developed and investigated. Disease-free and endemic equilibria of the model exist. The basic reproduction number was constructed by the method of next generation matrix. The global stability of the disease-free and endemic equilibria was discussed and shown to be asymptotically stable. The effects of the treatment rate, the recovery rate with complete immunity, and the risk mitigation factor were thoroughly discussed. Future work may include using the optimum control theory to mitigate hepatitis B infection.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "References\n\nCastillo-Chavez C, Song B: Dynamical models of tuberculosis and their applications. Math. Biosci. Eng. 2004; 1(2): 361–404. PubMed Abstract | Publisher Full Text\n\nCDC: see forHepatitis B Fact sheet No. 2, 2019.Reference Source\n\nCiupe SM, Ribeiro RM, Nelson PW, et al.: Modeling the mechanisms of acute hepatitis B virus infection. J Theor Biol. 2007; 247(1): 23–35. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFatehi Chenar F, Kyrychko YN, Blyuss KB: Mathematical model of immune response to hepatitis B. J Theor Biol. 2018; 447(March): 98–110. PubMed Abstract | Publisher Full Text\n\nKhan T, Ahmad S, Zaman G: Modeling and qualitative analysis of a hepatitis B epidemic model. Chaos. 2019; 29(10). PubMed Abstract | Publisher Full Text\n\nLau GKK, Cooksley H, Ribeiro RM, et al.: Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B. Antivir Ther. 2007; 12(5): 705–718. Reference SourcePubMed Abstract\n\nLaSalle JP: The Stability of Dynamical Systems, Regional Conference Series in Applied Mathematics, SIAM, Philadelphia, Pa,USA.1976.\n\nLong C, Qi H, Huang SH: Mathematical modeling of cytotoxic lymphocyte-mediated immune response to hepatitis B virus infection. J Biomed Biotechnol. 2008; 2008: 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMpeshe SC, Nyerere N: Modeling approach to assess the transmission dynamics of Hepatitis B infection in Africa Modeling approach to assess the transmission dynamics of Hepatitis B infection in Africa.March 2019.\n\nPang J, Cui JA, Zhou X: Dynamical behavior of a hepatitis B virus transmission model with vaccination. J Theor Biol. 2010; 265(4): 572–578. PubMed Abstract | Publisher Full Text\n\nPan CQ, Zhang JX: Natural History and Clinical Consequences of Hepatitis B Virus Infection. Int J Med Sci. 2005; 2(1): 36–40. Reference SourcePubMed Abstract | Publisher Full Text | Free Full Text\n\nvan den Driessche P, Watmough J: Reproduction number and subthreshold endemic equilibria for compartmental models of disease transmission. Math. Biosci. 2002; 180, 29–48. PubMed Abstract | Publisher Full Text\n\nQesmi R, Wu J, Wu J, et al.: Influence of backward bifurcation in a model of hepatitis B and C viruses. Math Biosci. 2010; 224(2): 118–125. PubMed Abstract | Publisher Full Text\n\nWang K, Fan A, Torres A: Global properties of an improved hepatitis B virus model. Nonlinear Analysis: Real World Applications. 2010; 11(4): 3131–3138. Publisher Full Text\n\nWHO: see for Hepatitis B Fact sheet No. 204.2019Reference Source\n\nWHO: see for Hepatitis B Fact sheet No. 133.2020Reference Source"
}
|
[
{
"id": "90565",
"date": "16 Aug 2021",
"name": "Abimbola Abolarinwa",
"expertise": [
"Reviewer Expertise Differential equations",
"Differential Geometry"
],
"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 develop and investigate the dynamic of HBV-model incorporating spontaneous clearance of acute individuals and recovery pf chronic individuals with full immunity. The model is subjected to sensitivity and stability analysis.\nThe results are well presented and discussed. I can recommend this paper for indexing if the authors can consider these suggestions:\nUnder Abstract - change positivity solution to positivity of solutions\n\nUnder Introduction - line 3 - change reporting to reported. Paragraph 4 - should be put in proper perspective to show the gap which this paper is trying to bridge. In my understanding, testing and treatment have always been part of epidemic (including HBV) control. You can advertise the novelty introduced in the paper. The statement \"The aim of this study is to contribute .....\" can be recast to make the aim measurable and specific to indicate what and what is being contributed and the its importance.\n\nUnder model implementation.\nLemma 1 -\nStart the statement with \"Suppose the initial values are ...\" No need for the word parameters\n\nNo need for $\\in \\Phi$ or $\\Phi$ should be defined\n\nThe solution of the model (3) {...} is posively invariant for all t>0. (not greater than or equal to).\nUnder the proof The last three line on page 4(so also the first 4 lines on page 5) should be corrected\nThese two lines can help in each case \"we have $$\\frac{dS}{dt} \\ge -(\\lamda_s+\\mu)S$$ and $$S(t)\\ge s_0e^{-\\lambda+\\mu)t.$$ (t should be included in power of e) where $s_0=S(0)\\ge 0$.\nHence S(t)> 0 for all t>0.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7309",
"date": "21 Jan 2022",
"name": "Olajumoke Oludoun",
"role": "Author Response",
"response": "All the comments have been attended to in the new version submitted"
}
]
}
] | 1
|
https://f1000research.com/articles/10-429
|
https://f1000research.com/articles/11-75/v1
|
21 Jan 22
|
{
"type": "Brief Report",
"title": "Circulating tumor cells isolated from colorectal cancer patients can form spheroids spontaneously: a small study in Ciptomangunkusumo Hospital, Indonesia",
"authors": [
"Murdani Abdullah",
"Dimas R. Noor",
"Hasan Maulahela",
"Saskia Aziza Nursyirwan",
"Dimas R. Noor",
"Hasan Maulahela",
"Saskia Aziza Nursyirwan"
],
"abstract": "Background: Circulating Tumor Cells (CTC) are tumor cells that have been separated from the primary site and enter the blood or lymphatic circulation of cancer patients. CTCs are known to have tumorigenic properties and are thought to have a relationship with metastasis. One of the tests that can be used to assess tumorigenesis is the spheroid formation test. This study was conducted to determine CTCs’ ability to form spheroids. Methods: A 1 ml sample of blood was taken from two patients with metastatic colorectal cancer and placed in separate heparin tubes. The CTCs were then isolated using the DirectCTC enrichment kit according to the manufacturer's procedure. A total of 10,000 cells were grown in nuncsphera u plates in Dulbecco’s Modified Eagle Medium (DMEM) for three days under standard culture conditions. Spheroid or aggregation was then evaluated using an inverted microscope. Results: We identified a CTC culture derived from each of the patients with metastatic colorectal cancer, namely CTC ID001 and CTC 002 respectively. CTC ID001 formed spheroids spontaneously while CTC ID002 did not. CTC ID001 appears to aggregate spontaneously and resembles primary tumor cells in their ability to form spheroids. Conclusions: We observed that CTCs can mimic primary tumors to form spheroids spontaneously, though some CTCs are not able to form spheroids. We suspected that this was related to the tumorigenic nature of CTC in these patients.",
"keywords": [
"Circulating Tumor Cell (CTC)",
"Colorectal Cancer",
"Primary Culture",
"Spheroid Culture"
],
"content": "Introduction\n\nCirculating Tumour Cells (CTCs) are commonly defined as tumour cells that enter circulating systems such as the blood or lymphatic vessels Grover et al., 2014). CTCs are cells that shed from either primary tumors or from metastatic sites (Wang et al., 2018). Recently, CTCs have been found to initiate tumorigenesis in Patient-Derived Xenograft models (Rodrigues and Vanharanta, 2019). Therefore, CTC might play a key role in understanding such metastatic processes (Castro-Giner and Aceto, 2020).\n\nThe tumorigenic capacity of CTC may be demonstrated using xenograft models as previously described (Rodrigues and Vanharanta, 2019) or by tumor spheroid formations in in vitro assay (Hu et al., 2021). However, xenograft models and 3D culture using Matrigel cell culture matrix is expensive, in particular for developing countries such as Indonesia. In this study, we report the interesting findings from our pilot study that show CTCs were able to be cultured and that they can form spheroid aggregations spontaneously. Therefore, such methods may be promising and should be further investigated, in particular in developing an economical assay to test the tumorigenesis ability of CTCs. This pilot study is a part of a larger study that aims to assess CTC as a diagnostic tool for colorectal cancer (CRC).\n\n\nMethods\n\nThis pilot study is a part of a larger study that was approved by the Ethical Committee of Faculty of Medicine, Universitas Indonesia (Protocol ID: 20-04-0643, version 02, June 29th, 2020). Recruited subjects provided their written informed consent for blood donation (biobanking) and for the use and publication of their data for research purposes. All participants signed an informed consent form before participating in the study. In addition, the two patients involved in this pilot study provided written informed consent for participation and publication of their data.\n\nPatient blood samples were taken in the endoscopy room of the Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Isolation and culture were carried out at the Indonesian Institute of Medical Research and Education, Faculty of Medicine, University of Indonesia. Subjects were recruited (as part of the overarching study) from June 2020 until the culture process was carried out in August/September 2020. Primary culture images were taken separately in August 2021.\n\nA total of 73 patients with colorectal cancer, who were older than 18 years old and who were scheduled for colonoscopy were recruited for the overarching study. After patient consent was obtained, demographic and clinical data were collected from each patient. The demographic data included gender and age, and the clinical data included cancer location, stage, and metastasis. Histological data (cancer type, differentiation) were also noted. Then, 2 ml of patient blood were drawn from a peripheral vein (cubiti vein) and transferred in BD vacutainer (Becton, Dickinson and Company, USA, www.bd.com) heparinized tubes. During the recruitment process for the overarching study, we observed two patients with similar metastatic features and included these patients in the CTC pilot study.\n\nTo obtain the CTCs for this pilot study, two colorectal cancer patients who had similar clinical profiles, namely liver metastases (see Table 1) were chosen. Approximately 1 ml of blood was taken from each patient and placed in separate heparin tubes. The blood was then transferred from the heparin tubes to separate polypropylene tubes to undergo CTC isolation using Easysep™ Direct Human CTC Enrichment kit (Catalog #19657, StemCell Technologies, Canada), according to the manufacturer's protocol. The enriched cells were then pooled in 15 ml centrifuge tubes and centrifuged 300 × g for five minutes. Supernatant was removed afterward. Cell pellets were resuspended in 1 ml complete Dulbeco’s Modified Eagle medium (Gibco, USA) supplemented with 10% Fetal Bovine Serum (Gibco, USA) and 1% of Antibiotic-antimycotic solution (Gibco, USA).\n\nThe process of spheroid formation was carried out by implanting cells directly on the nuncsphera u-plates and allowing the cells to immediately aggregate at the bottom of the plate. Approximately 10,000 isolated cells of colorectal CTC’s primary cells were seeded directly in Nunclon™ Sphera™ 96-Well, Nunclon Sphera-Treated, U-Shaped-Bottom Microplate (Catalog number: 174929) (Thermoscientific, USA) and incubated under standard culture conditions (37 °C, 5% CO2) for three days. For controls, we seeded 5,000 cells of primary breast cancer culture, obtained from the Human Cancer Research Center, Indonesia Medical Education, and Research Institute. This culture was originally collected for optimizations of primary cultures and was obtained from discarded tissues. Written informed consent was provided by the patient for this purpose. All spheroids were examined using Carl Zeiss inverted microscope using 10× magnification in Zen blue 2.1 embedded software (Carl Zeiss, Germany).\n\n\nResults\n\nIn this study, we identified two patients with similar clinical profiles which rectal adenocarcinoma and metastatic cancer in the liver. The demographic information of the two patients is shown in Table 1. At first glance, we wanted to optimize the culture conditions for CTC of the metastatic cancer patients in the short term for approximately 3-7 days using standard culture media. The first question we wished to address was how the CTC culture had grown in vitro under standard culture conditions. Our suggestion was to increase the chance of cell-to-cell contact using 3D cultures.\n\nIn this study, we were able to identify two cultures from two patients, namely ID 001 and ID 002 after three days of incubation. Surprisingly, we found that ID 001 was able to form aggregation of cells (Figure 1A) while the CTC 002 did not have aggregation formation (Figure 1B). The ID 002 displayed clustered grape-like morphology. Therefore, we suspected that the aggregation formation may vary between samples and may depend on intrinsic factors between samples such as homophilic interactions of Cluster of Differentiation (CD)-44/CD44 antigen/CD44 that induced multicellular aggregations.\n\n(A) The CTC with ID001 was able to spontaneously aggregate at the bottom of the well, forming a spheroid aggregation. (B) The CTC with ID 002 was unable to form uniform aggregation.\n\nSince tumors are known for their ability to form aggregations, we chose an aggressive solid type of tumor, namely breast cancer as a control for the study. Breast cancer was a type of solid tumor with a known lobular structure and estimated behold potency to form aggregation in the 3D culture platform. We tried to seed these primary cells directly to the same type of plates used for the CTCs, for the duration of three days. We found that this produced a more rigid structure of spheroid formation (as shown in Figure 2).\n\nThe primary breast cancer cultures derived from primary tumor were able to form spontaneous spheroid formations after three days culture. This is one of the characteristics of tumor cells.\n\n\nDiscussion\n\nIn this study, we wanted to know the characteristics of isolated CTC cells by observing the ability of isolates to form spheroids. Based on this study, it was shown that CTC can form spheroids spontaneously. We recommend using an u-plate for the test to allow the aggregation process at the bottom of the plate. After that, it is recommended that the sample be left for three days. Our results showed that, surprisingly, CTC ID 001 had the ability to spontaneously form spheroids within three days, whereas CTC ID 002 did not spontaneously form spheroids (Figure 1).\n\nThe spheroid formation has been found as in vitro assay to evaluate the tumorigenic capacity of the cells (Hu et al., 2021) In this study, we found facts that CTC was able to form spheroids and aggregations. Therefore we suspected that CTCs might have some tumorigenic capacity, which may be displayed by the aggregations. We confirmed these aggregation processes in primary breast cancer cells using the same methods and observed a more dense and darker spheroid formation (Figure 2). Thus, the aggregations may also be related to tumorigenesis of the CTCs or at least some similar features, as those primary cells were able to form spheroids.\n\nPreviously, the tumorigenicity of CTCs has been reported using Patient-Derived Xenograft (PDX) models (Rodrigues and Vanharanta, 2019). From our perspective, such conditions of spheroid formation may be related to the tumorigenic potential of CTC. At least, these CTC cultures were isolated from two metastatic colorectal cancer patients (shown in Table 1). Our results suggested that the CTCs have the ability to mimic primary tumors in their ability to spontaneously aggregate in vitro. The capacity of the CTC to form aggregation may vary depending on intrinsic factors such as expressions of CD44 in the CTC’s that could not be identified in this study. A previous study by Liu et al. showed that homophilic interactions between CD44 increase the chance of cell to cell contact, leading to multicellular aggregations of the patient-derived breast cancer models (Liu et al., 2019). In the future, we suggest that our findings regarding spheroid aggregation assay may be used as a potential alternative to predict either patient metastasis or tumorigenic capacity of CTC in a larger study.\n\n\nData availability\n\nOpen Science Framework: Circulating Tumor Cells from CRC CIptoMangunkusumo. https://doi.org/10.17605/OSF.IO/7CGYA (Abdullah, 2021).\n\nThis project contains the following underlying data:\n\n- Figure 1A. tiff (CTC ID 001 ability to spontaneously form spheroid aggregation in vitro)\n\n- Figure 1B. tiff (CTC ID 002 3D culture formations, which could not spontaneously form aggregation)\n\n- Figure 2. tiff (Breast cancer primary cells’ ability to form spheroid aggregation in vitro)\n\n- Table 1. Patient demographic.xlsx\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 Dr. Nadhira Nizam and Dr. Asiyah Nurul Fadilah for their valuable contribution in gathering patients and samples resources. We also thank Dr Erwin Danil from Department of Surgery Oncology CiptoMangunkusumo Hospital and Human Cancer Research Center for supporting the development of breast cancer primary culture.\n\n\nReferences\n\nAbdullah M: Circulating Tumor Cells from CRC CIptoMangunkusumo.2021, November 9. Publisher Full Text\n\nCastro-Giner F, Aceto N: Tracking cancer progression: from circulating tumor cells to metastasis. Genome Med. 2020; 12: 31. PubMed Abstract | Publisher Full Text\n\nGrover PK, Cummins AG, Price TJ, et al.: Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann. Oncol. 2014; 25: 1506–1516. PubMed Abstract | Publisher Full Text\n\nHu C-L, Zhang Y-J, Zhang X-F, et al.: 3D Culture of Circulating Tumor Cells for Evaluating Early Recurrence and Metastasis in Patients with Hepatocellular Carcinoma. OncoTargets Ther. 2021; 14: 2673–2688. PubMed Abstract | Publisher Full Text\n\nRodrigues P, Vanharanta S: Circulating Tumor Cells: Come Together, Right Now, Over Metastasis. Cancer Discov. 2019; 9: 22–24. PubMed Abstract | Publisher Full Text\n\nWang W-C, Zhang X-F, Peng J, et al.: Survival Mechanisms and Influence Factors of Circulating Tumor Cells. BioMed Res. Int. 2018; 2018: 1–9. PubMed Abstract | Publisher Full Text\n\nLiu X, Taftaf R, Kawaguchi M, et al.: Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models. Cancer Discov. 2019; 9(1): 96–113. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "126764",
"date": "11 Apr 2022",
"name": "Arutha Kulasinghe",
"expertise": [
"Reviewer Expertise Liquid biopsy",
"CTCs",
"tumour microenvironment"
],
"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 aimed to expand and characterise CTCs through a culture protocol. The authors report on a low culture success, yet there are concerns around what these cells are as they have not been molecularly profiled.\nI think the manuscript still needs major amendments – specifically below:\nThis study recruited 73 patients, but only 2 patient's samples were attempted to be cultured? Can the authors justify this? The sample size and variability is too high. Previous CTC culture studies have shown low culture success - with 2 samples, this is too preliminary. What about the remaining 71 patient samples? Are there reasons as to why the authors think that cultures were not possible?\nThere is no confirmation that these are indeed CTCs, other than cells clustering, can these be WBCs? Non cancer cells? Molecular confirmation of CTCs by DNA fish of similar should be applied, at least multiplex IF staining of clusters. The authors need to confirm that these are indeed CTCs and not any other cell type selected for by expansion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Partly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "181833",
"date": "01 Aug 2023",
"name": "Sharmin Aktar",
"expertise": [
"Reviewer Expertise Liquid Biopsy",
"CTCs",
"Cancer Molecular 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\nThe content of the article is promising and holds potential significance for the scientific community. However, to strengthen the findings, further clarification and improvements are needed.\nThe author utilized the CTC direct human enrichment kit, which may not completely deplete leukocytes. How did you confirm the presence of CTCs among the contaminating leukocytes? To enhance the study's credibility, the author should provide the evidence for accurate CTC identification.\n\nTo bolster the hypothesis of spheroid tumorigenic capacity, the author could conduct a cell function assay. This additional experiment would provide valuable evidence and strengthen the overall conclusions.\n\nWhile the study's premise is intriguing, the background information needs further clarification. Expanding on the context and rationale behind the research would enhance reader understanding and engagement.\n\nThe methods section requires more comprehensive organization and information.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-75
|
https://f1000research.com/articles/11-74/v1
|
21 Jan 22
|
{
"type": "Clinical Practice Article",
"title": "Complex psychiatric comorbidities in Thai trans women: A case series",
"authors": [
"Sorawit Wainipitapong",
"Soravit Burakitpachai",
"Thanapob Bumphenkiatikul",
"Sorawit Wainipitapong",
"Soravit Burakitpachai"
],
"abstract": "Trans women (TW) have a high prevalence of poor mental health. Gender-affirming treatments could reduce distress regarding their gender incongruity. However, psychiatric comorbidities might complicate the management or even confirmation of being transgender. We reported three TW with complex mental illnesses, including anxiety disorder with cultural explanation, neurodevelopmental disorders with cross-dressing, and severe personality disorder accompanied by major depression. All cases received both psychiatric and gender-affirming treatments, which demonstrated promising outcomes. Along with gender dysphoria (GD), psychiatric comorbidities also altered these TW’s identity and manifestations. Recognition of such conditions would be beneficial in providing care for all TW, both with and without GD.",
"keywords": [
"Transwomen",
"gender dysphoria",
"psychiatric disorder",
"mental illness",
"Case Study",
"Gender Dysphoria",
"Transgender",
"Mental Health",
"Gender Identity Disorder (GID)",
"Trans"
],
"content": "Introduction\n\nCompared to the cisgender population, transwomen (TW) are at higher risk of developing mental disorders, including anxiety and affective disorders, suicidality, and substance abuse (Schulman & Erickson-Schroth, 2019). Gender-affirming treatments could alleviate their distress but, even following gender transition, TW remain at greater risk of mental health issues (Jellestad et al., 2018). Stigmatization, both interpersonally and at a larger social level, is considered to be the leading cause of psychiatric disorders among TW (Verbeek et al., 2020). From a young age, TW often experience bullying and discrimination at school and have been prohibited from expressing their gender identity, such as through wearing feminine uniforms or hairstyles due to the Thai educational policy. Some TW discontinued their education as a result and practiced sex work due to lower educational level and discrimination (de Lind van Wijngaarden & Fongkaew, 2020).\n\nAdditionally, TW can suffer from gender dysphoria (GD) (Zucker et al., 2016). As well as being a consequence of gender incongruity, some psychiatric conditions could mask GD manifestation and interfere with diagnoses of GD. Gender identity development is affected by both biological and psychological factors (Steensma et al., 2013). Psychiatric disorders with biological or psychological origin can also influence identity formation and expression. Moreover, feelings of shame, which inhibit clients’ self-disclosure in order to avoid social discrimination, are more frequently found in Asian cultures compared to Western cultures (Bedford & Hwang, 2003). Therefore, fear of social rejection can prevent TW from disclosing their genuine gender identity to their peers or even family members (Huang et al., 2020). Providers in TW healthcare could find difficulties in complex psychiatric comorbidities and cultural considerations in diagnoses, treatment planning, gender-affirming therapy, and psychological interventions.\n\nIn this study, we portray the clinical experience of three TW with GD and psychiatric comorbidities at our Gender Health Clinic located in Bangkok, Thailand. All these clients were undergoing gender-affirming hormonal therapy (GAHT), which included regular hormonal prescription and pre-procedural psychological counselling. GD was diagnosed by a psychiatrist according to the DSM-5 criteria and psychiatric follow-ups were provided as appropriate. An initial evaluation was conducted to identify those who have contraindication for GAHT, such as active liver disease, hormone-responsive malignancy, or a history of venous thromboembolism. Clients with no contraindications would be prescribed with either transdermal or oral estrogen, and antiandrogen for TW with intact gonads. Clients would be monitored every three months to ensure the safety and efficacy of the treatment. Once their condition is stable, the visit would be every 6-12 months for holistic health surveillance. TW healthcare providers should recognize these patterns so that proper evaluation and holistic care can be delivered to our TW clients.\n\n\nCases\n\nTW1 is a 37-year-old Thai engineer from Bangkok. She had been married for four years before visiting our clinic. Brought up in a large Thai-Chinese, multigenerational family, she had carried expectations from her family to continue the family linage. She was sent to a boys’ school and was bought up as a boy. At that time, she reported a sense of maleness and had relationships with women. After her graduation, she worked as an engineer and married her female spouse two years later. Afterwards, she and her wife moved out from her former residence and lived away from her family. She found her authentic femininity following the birth of her son and the experience of becoming a parent for the first time. Independence from her family values gradually revealed masked anxiety as a result of conflict between her genuine gender and traditional Asian social expectations. Fears of discrimination and worrying about the consequences of stigmatization was consciously exhibited and manifested as anxiety symptoms, which GD also contributed to. She ultimately decided to undergo her transition at the age of thirty-five. She has now received GAHT and psychological counselling, which has remarkably improved her distress as well as family problems. Even though her family hoped for a lineal descendent, they also wanted her to be happy and who she truly is.\n\nGD typically manifests very early in childhood (Zaliznyak et al., 2020). Onset GD in TW is most commonly found among adolescents after puberty, and less frequently in adulthood (Zucker et al., 2016). Two crucial points should be mentioned on whether the onset of GD represented being a TW or was additional to this. Those with late-onset GD may prioritize career achievement rather than early transition or have concerns around social discrimination (Zavlin et al., 2019). However, delayed onset of GD has received less academic attention. TW1 demonstrated prolonged repressed femininity influenced by Asian family values, which expect the continuation of the patriarchal family line (Berry, 2001). Negative attitudes toward gender minorities are highly prevalent in the Asian context as displayed in the case here. We identified increasing psychological distress in families with lower gender-related support but higher gender-related discrimination (Fuller & Riggs, 2018; Xie & Peng, 2018). Multidimensional assessment, including family evaluation based on specific cultural belief, should be considered in TW such as our client with adulthood onset GD (Silveira et al., 2016).\n\nTW2 is a 22-year-old TW, studying computer graphic design in Bangkok. She was the only child with a history of being bullied and discriminated against. She was diagnosed with attention deficit/hyperactivity disorder and major depression in childhood. After receiving psychiatric treatment, her symptoms partially improved, but conflicts among her family remained. She frequently had arguments with her mother, who was over-involved in most of her decision-making. Her father was distant and invariably not involved in these disputes. Because of problems at school and with family, she gradually developed more feelings of inadequacy and low self-esteem. It wasn’t until she won a cross-dressing competition at her school festival, that she felt for the first time that her parents were proud of their only son. Later on, she began to dress in feminine fashion, which she found to be her only method of self-soothing, and she was still interested in girls. However, when cross-dressing, she found her male appearance incongruous with her identity, so she began taking oral contraceptive pills to become more feminine. At her age of twenty, her mother was concerned and brought her to our clinic. At the first visit, she appeared in feminine cut shoes and had difficulties in communication with poor eye contact. Because of her communication difficulties, the primary diagnoses were autism spectrum disorder (ASD) and transvestism, with GD as a differential diagnosis. After sessions of counseling and psychoeducation, she was able to describe more about her identity, which was found to be feminine. Her sexual orientation expanded from gynephilia to any gender, and transvestism was replaced with GD three months after her first visit. She then received GAHT which she was satisfied with and had minimal tolerable side effects. She and her family noted the resolution of her distress and improved affect regulation, which lessened her family conflicts.\n\nTW2 presented an interesting case of GD with co-occurring ASD. The ASD population has greater numbers of gender diversity than the general population (Glidden et al., 2016). Compared to the cisgender population, previous studies consistently found a higher prevalence of neurodevelopmental disorders, including ASD, among transgender people (Heylens et al., 2018; Strauss et al., 2021). Specifically, ASD is more common in TW than in transmasculine individuals (Strang et al., 2018). Difficulties in communication and self-understanding regarding their identities and sexual desires make it challenging for providers of transgender healthcare to diagnose GD, therefore more extended periods for evaluation before gender-affirming therapy are required. As presented in our client who has experienced multiple psychosocial problems accompanied by ASD, several psychiatric comorbidities are more common among TW with ASD than those without ASD (Strauss et al., 2021). Clinicians taking care of GD and ASD individuals should be aware of these co-occurrences in order to provide comprehensive mental health surveillance among this population.\n\nTW3 is a twenty-four-year-old trans lesbian (homosexual TW) living in Bangkok and working as a programmer. After her parents divorced during her infancy, she was brought up by her mother and two elder sisters. Her kindergarten teacher reported her feminine expression to her mother; from then on, she had to suppress her identity to prevent social stigmatization and opposition from family. With little family support, she was forced to engage with entirely male peers, was still interested in women, and became ordained into the Buddhism monkhood as her mother wished. She left her family to go to boarding high school and studied abroad afterwards. During this time, she found herself more comfortable and was able to express her identity freely. However, she then moved back to Thailand, worked as a programmer, and lived alternately with her family and girlfriend. Severe depressive symptoms, including multiple suicidal attempts, gradually arose as a result of relationship problems, discrimination, and her internalized homophobia. She was hospitalized with major depression and borderline personality disorder and referred to our clinic for her previously diagnosed GD. Alongside several psychotropic medications, individual and group psychotherapies, and even electroconvulsive therapy, she has been prescribed GAHT but has reported only a marginal improvement in her conditions.\n\nBorderline personality disorder is a complicated psychiatric disorder presenting affective and relationship instability that always coexists with other mental morbidities (Paris, 2018). GD and major depression are related in patients with borderline personality and cause emotional regulation difficulties, early life stress and abuse, and identity disturbances along with a higher prevalence of homosexuality (Carvalho Fernando et al., 2014; Frías et al., 2016). Unstable self-identity also complicates the diagnosis of GD and requires careful history taking and frequent updates to the patients’ information (Goldhammer et al., 2019). TW with identity problems should be screened for comorbid borderline personality because gender-affirming therapy alone without psychiatric treatments, and vice versa, may result in poorer outcomes (Smith et al., 2019). However, determining the severity of psychopathology is essential to the treatment prognoses presented in TW3.\n\n\nConclusion\n\nThese case reports demonstrate complex psychiatric comorbidities with GD, which could be underrecognized and untreated. Our cases’ patterns might be common and beneficial in terms of early recognition. However, some limitations including cultural differences should be considered in our study’s generalizability.\n\nIn the context of Asian culture and tradition, Thai TW have experienced great internal stigmatization and social discrimination (de Lind van Wijngaarden & Fongkaew, 2020), which can result in secondary anxiety and delay the timing of identity disclosure and even their own identity recognition. Neurodevelopmental disorders often co-occur and interfere with gender identity development. Communication deficit among the patients could obscure diagnoses of GD and related conditions. Borderline personality disorder often relates to identity disturbance, including gender identity and sexual orientation. TW with borderline personality disorder represent the diversity of sex and gender due to their identity disturbance and highlight the factors that should be considered in treatment. Healthcare providers for TW should be aware of complex psychiatric comorbidities in order to prescribe holistic gender-affirming interventions. Appropriate psychiatric referral is recommended to promote broader physical and mental dimensions of healthcare for all TW.\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 clients.\n\n\nEthical approval\n\nThis report was exempted by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. (COE No.050/2021) Date of exemption: September 28, 2021.\n\n\nAuthor contributions\n\nSorawit Wainipitapong: Conception and design of the study, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the completed article;\n\nSoravit Burakitpachai: Acquisition of data, Analysis and interpretation of data, Drafting the article;\n\nThanapob Bumphenkiatikul: Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content.",
"appendix": "Acknowledgements\n\nWe thank all clients whose shared stories are valuable for transgender healthcare providers.\n\n\nReferences\n\nBedford O, Hwang K-K: Guilt and Shame in Chinese Culture: A Cross-Cultural Framework from the Perspective of Morality and Identity. J. Theory Soc. Behav. 2003; 33: 127–144. Publisher Full Text\n\nBerry C: Asian values, family values: Film, video, and lesbian and gay identities. J. Homosex. 2001; 40(3–4): 211–231. Publisher Full Text\n\nCarvalho Fernando S, Beblo T, Schlosser N, et al.: The impact of self-reported childhood trauma on emotion regulation in borderline personality disorder and major depression. Journal of Trauma & Dissociation: The Official Journal of the International Society for the Study of Dissociation (ISSD). 2014; 15(4): 384–401. PubMed Abstract | Publisher Full Text\n\nde Lind van Wijngaarden JW , Fongkaew K: “Being Born like This, I Have No Right to Make Anybody Listen to Me”: Understanding Different Forms of Stigma among Thai Transgender Women Living with HIV in Thailand. J. Homosex. 2020; 68: 2533–2550. PubMed Abstract | Publisher Full Text\n\nFrías Á, Palma C, Farriols N, et al.: Sexuality-related issues in borderline personality disorder: A comprehensive review. Personal. Ment. Health. 2016; 10(3): 216–231. PubMed Abstract | Publisher Full Text\n\nFuller KA, Riggs DW: Family support and discrimination and their relationship to psychological distress and resilience amongst transgender people. Int. J. Transgenderism 2018; 19(4): 379–388. Publisher Full Text\n\nGlidden D, Bouman WP, Jones BA, et al.: Gender Dysphoria and Autism Spectrum Disorder: A Systematic Review of the Literature. Sex. Med. Rev. 2016; 4(1): 3–14. PubMed Abstract | Publisher Full Text\n\nGoldhammer H, Crall C, Keuroghlian AS: Distinguishing and Addressing Gender Minority Stress and Borderline Personality Symptoms. Harv. Rev. Psychiatry. 2019; 27(5): 317–325. PubMed Abstract | Publisher Full Text\n\nHeylens G, Aspeslagh L, Dierickx J, et al.: The Co-occurrence of Gender Dysphoria and Autism Spectrum Disorder in Adults: An Analysis of Cross-Sectional and Clinical Chart Data. J. Autism Dev. Disord. 2018; 48(6): 2217–2223. Publisher Full Text\n\nHuang Y-P, Wang S-Y, Kellett U, et al.: Shame, Suffering, and Believing in the Family: The Experiences of Grandmothers of a Grandchild With a Developmental Delay or Disability in the Context of Chinese Culture. J. Fam. Nurs. 2020; 26(1): 52–64. PubMed Abstract | Publisher Full Text\n\nJellestad L, Jäggi T, Corbisiero S, et al.: Quality of Life in Transitioned Trans Persons: A Retrospective Cross-Sectional Cohort Study. Biomed. Res. Int. 2018; 2018: 1–10. PubMed Abstract | Publisher Full Text\n\nParis J: Differential Diagnosis of Borderline Personality Disorder. Psychiatr. Clin. North Am. 2018; 41(4): 575–582. Publisher Full Text\n\nSchulman JK, Erickson-Schroth L: Mental Health in Sexual Minority and Transgender Women. Med. Clin. North Am. 2019; 103(4): 723–733. Publisher Full Text\n\nSilveira MT, Knobloch F, Silva Janovsky CCP, et al.: Gender Dysphoria in a 62-Year-Old Genetic Female With Congenital Adrenal Hyperplasia. Arch. Sex. Behav. 2016; 45(7): 1871–1875. PubMed Abstract | Publisher Full Text\n\nSmith WB, Goldhammer H, Keuroghlian AS: Affirming Gender Identity of Patients With Serious Mental Illness. Psychiatric Services (Washington, D.C.). 2019; 70(1): 65–67. PubMed Abstract | Publisher Full Text\n\nSteensma TD, Kreukels BPC, de Vries ALC , et al.: Gender identity development in adolescence. Horm. Behav. 2013; 64(2): 288–297. Publisher Full Text\n\nStrang JF, Meagher H, Kenworthy L, et al.: Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents. Journal of Clinical Child and Adolescent Psychology: The Official Journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53. 2018; 47(1): 105–115. Publisher Full Text\n\nStrauss P, Cook A, Watson V, et al.: Mental health difficulties among trans and gender diverse young people with an autism spectrum disorder (ASD): Findings from Trans Pathways. J. Psychiatr. Res. 2021; 137: 360–367. PubMed Abstract | Publisher Full Text\n\nVerbeek MJA, Hommes MA, Stutterheim SE, et al.: Experiences with stigmatization among transgender individuals after transition: A qualitative study in the Netherlands. Int. J. Transgender Health. 2020; 21(2): 220–233. PubMed Abstract | Publisher Full Text\n\nXie Y, Peng M: Attitudes Toward Homosexuality in China: Exploring the Effects of Religion, Modernizing Factors, and Traditional Culture. J. Homosex. 2018; 65(13): 1758–1787. PubMed Abstract | Publisher Full Text\n\nZaliznyak M, Bresee C, Garcia MM: Age at First Experience of Gender Dysphoria Among Transgender Adults Seeking Gender-Affirming Surgery. JAMA Netw. Open. 2020; 3(3): e201236. PubMed Abstract | Publisher Full Text\n\nZavlin D, Wassersug RJ, Chegireddy V, et al.: Age-Related Differences for Male-to-Female Transgender Patients Undergoing Gender-Affirming Surgery. Sex. Med. 2019; 7(1): 86–93. PubMed Abstract | Publisher Full Text\n\nZucker KJ, Lawrence AA, Kreukels BPC: Gender Dysphoria in Adults. Annu. Rev. Clin. Psychol. 2016; 12: 217–247. Publisher Full Text"
}
|
[
{
"id": "123259",
"date": "28 Mar 2022",
"name": "Awirut Oon-Arom",
"expertise": [
"Reviewer Expertise psychiatry"
],
"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 interesting complex psychiatric cases of transgender women (TGW) in several aspects. The article demonstrates the complicated neurodevelopment disorder (Autism spectrum disorder) and gender dysphoria. Although both disorders are widely reported as dual-diagnosis or concurrent disorder, the consequence of delayed diagnosis and management were rarely discussed. This article also highlighted the diversity of sexual orientation in TGW that might related to personality components such identity disturbance of borderline personality disorder.\nHowever, there are a couple of minor comments the authors might wish to consider:\nIn terms of mental health outcomes, one of the important mental health is depression and quality of life. There is a report about bullying experience, depression, and quality of life among TGW. Please consider additional discussion citations in this topics. 12\nOther common health risks among gender minority and borderline personality trait or disorder are substance use and sexual health problems. Increased substance use, across most substances, is found among PD and gender & sexual diverse people. Discussion more on these problems/ different patterns of substance use would widen the perspectives of TW3 and might lead the readers to concern more in psychiatric evaluation among these unique population.34\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes",
"responses": []
},
{
"id": "160175",
"date": "25 Jan 2023",
"name": "Gonzalo R Quintana",
"expertise": [
"Reviewer Expertise Sexual behavior and function in animals and people."
],
"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 provides a good description of a rarely studied phenomena of psychiatric comorbidity amongst transgender women. They provide valuable evidence on a research area with limited information, where cases analysed from a cultural perspective is highly necessary, and review succinctly, but effectively, the phenomenon of gender dysphoria with relevant citations and authors. The article provides a balanced discussion of each case, especially when considering culture as a determinant factor in each case.\nTheir report reads well and fluently. There are minor details highlighted and suggestions below.\nAll three cases are adults, between younger and emerging, and middle-age. As pointed out by the authors, GD is most commonly found in adolescence. Therefore, I believe the authors should develop more this aspect of their cases in the conclusions, especially how it factors in the other psychiatric comorbidities. This is a key aspect of their cases that deserves a deeper analysis, especially for future cases.\nMinor comments:\n\"Additionally,\" is not a good word to begin a paragraph. It may be taken out, and perhaps be replaced by the word \"also\", namely, \"TW can ALSO suffer from...\"\nWhere it says \" GD, therefore more...\" the comma can very well be changed by a dot.\nAuthors should consider enlightening the reader with other studies regarding other psychiatric comorbidities (e.g., mood disorder) with bigger samples of trans people (e.g. Wanta JW, Niforatos JD, 2019; Reisner SL, Biello KB, 2016).1,2\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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-74
|
https://f1000research.com/articles/11-73/v1
|
21 Jan 22
|
{
"type": "Research Article",
"title": "Screening patients with metastatic breast cancer for psychiatric disease: a cross sectional study",
"authors": [
"Raquel Basto",
"Cecília Caramujo",
"Inês Ferreira Gomes",
"Teresa Fraga",
"Joana Correia Magalhães",
"Maria João Sousa",
"Sabrina de Jesus",
"Ana Raquel Monteiro",
"Adriana Pestana-Santos",
"Teresa Carvalho",
"Emília Albuquerque",
"Gabriela Sousa",
"Cecília Caramujo",
"Inês Ferreira Gomes",
"Teresa Fraga",
"Joana Correia Magalhães",
"Maria João Sousa",
"Sabrina de Jesus",
"Ana Raquel Monteiro",
"Adriana Pestana-Santos",
"Teresa Carvalho",
"Emília Albuquerque",
"Gabriela Sousa"
],
"abstract": "Background: Cancer patients are at risk of developing some level of psychological dysregulation, depending on a series of variables related to the tumor, the environment, and the patient. In this context, it becomes important to define the difference between psychological and psychiatric disorder and to study its prevalence. The primary endpoint of this study is to evaluate the prevalence of psychiatric disorders in a sample of Portuguese patients with metastatic breast cancer and assess the relationship between these disorders and the characteristics of the oncological disease. Methods: Cross-sectional, single-center study with female patients diagnosed with metastatic breast carcinoma and under palliative treatment between November 2020 and May 2021. Psychiatric disorders were screened by applying and filling-out the MMSE, HADS, BSI, and WHOQoL-Bref instruments at the outpatient daycare unit when patients were present for treatmen. Results: A total of 91 female patients were included, median age 59.79 years. None of the patients had cognitive impairment (MMSE). HADS scale: 18.7% of the patients scored for anxiety and 17.6% for depression. The anxiety subscale score of > 8 (HADS) was related to ovarian function suppression (p<0.001), neoadjuvant therapy (p<0.001), and type of second-line of palliative treatment (p=0.024). The depression subscale score >8 (HADS) was related to the type of surgery performed (p= 0.022), molecular subtype of the tumor (p=0.020), and occurrence of grade 3-4 toxicities in the first (p=0.018), and third-line treatments (p=0.031). Conclusion: The screening of psychiatric disorders through the application of these scales by the medical oncology team may be able to aid in diagnosis and potentially lead to psychiatric referral and intervention at an earlier stage.",
"keywords": [
"oncology",
"psychiatric",
"disorder"
],
"content": "Introduction\n\nCancer is the second leading cause of death worldwide, after cardiovascular disease.1 In the 21st century, we have been witnessing a great evolution in oncology, both regarding our knowledge of cancer biology and physiopathology, as well as regarding its diagnosis and treatment. Still, cancer is regarded as an accelerated enhancer of suffering, uncontrolled pain, and death. This preconceived idea is directly related to some types of psychological disorders, regardless of the type of tumor and the stage at diagnosis.2,3 Therefore, cancer patients are at risk of developing some level of psychological dysregulation, depending on a series of variables related to the tumor, the environment, and the patient.4–6 In this context, it becomes important to define the difference between psychological and psychiatric disorder,7 since several studies have shown that there is a large percentage of cancer patients with psychological disorders7–9 but only a few meet the criteria for the diagnosis of psychiatric disorder.10,11 A few studies which surveyed the prevalence of psychiatric diagnoses in cancer patients have been conducted and demonstrated that the most frequent disorders were depression and anxiety.7,10 The correct and timely diagnosis of these disorders or diseases is of the utmost importance in order to help patients, since the absence of diagnosis, monitoring, and treatment of these pathologies can culminate in lack of treatment adherence and tolerance,12 lower survival rates,13 and decreased quality of life.14,15\n\nThere are several screening tools for psychological or psychiatric disorders validated for cancer patients. It is known that psychiatric morbidity affects women with breast cancer both in the initial and advanced stages,16 but few studies corroborate this. Furthermore, to the best of our knowledge, there are no data regarding the prevalence of psychiatric disorders in Portuguese patients with advanced breast cancer. Hence, our study aims to evaluate the prevalence of psychiatric disorders in a sample of Portuguese patients with metastatic breast cancer, as well as to assess the relationship between these disorders and the characteristics of the oncological disease.\n\n\nMethods\n\nWe conducted a cross-sectional, single-center study. The convenience sample was designed with inclusion criteria consisting of female patients 18 years of age or older, diagnosed with metastatic breast carcinoma under palliative treatment with chemotherapy, hormone therapy, cyclin inhibitors, or targeted anti-HER2 therapy, between November 2020 and May 2021, at the Medical Oncology Department of the Instituto Português de Oncologia de Coimbra Francisco Gentil, E.P.E. Exclusion criteria for the study were known brain metastasis, baseline cognitive impairment, refusal to participate in the study, and incomplete clinical records. The final sample size after included 91 of the initial 128 participants evaluated.\n\nPatients were recruited at the outpatient daycare unit when they were present for treatment. The application and filling-out of the various scales (Mini Mental State Examination (MMSE), HADS, BSI, and WHOQoL-Bref instruments) was conducted by the first author before treatment in order to minimize bias that could be developed in the post-treatment period. MMSE was the first instrument to be used, since a score compatible with cognitive impairment would represent and exclusion criteria. Afterwards, HADS, BSI and WHOQoL-Bref scales were applied through direct questioning of the patients and presentation of various possibilities of response, with repetition of each if solicited. The referral for the Psychiatry appointment was made whenever the HADS scale exceeded the cut-off score of 8 in each part of the instrument17 or when the BSI exceeded the cut-off of 1.7.18,19 The referred patients were posteriorly evaluated by an element of the psychiatric team consisting of two specialists, ideally within a month after the application of scales and at times within a week if the screening determined an elevated psychopathological risk. Determinants of elevated risk or severity included suicidal ideation and depressive symptoms with significant impact on daily functioning. The results, including possible diagnoses and eventual necessity of psychiatric medication from this evaluation were determined at this observation. The codification of psychiatric diagnoses was carried out using the International Classification of Diseases, Tenth Revision (ICD-10).\n\nThe following complementary data were collected either by direct questioning of the patient or consultation of the electronic files: gender; age; Eastern Cooperative Oncology Group – Performance Status (ECOG-PS); gynecological history; obstetric history; psychiatric; social history and characteristics of oncological disease.\n\nThe primary endpoints were assessing prevalence and type of psychiatric disorder and determining its relationship with characteristics of the oncological disease and treatment. Regarding secondary endpoints, quality of life (QoL) was evaluated.\n\nVarious scales were applied including MMSE which is the most widespread cognitive impairment/dementia screening tool.20 It is a brief 30-item measure that assesses six cognitive domains: visuospatial construction, language function, attention and concentration, working memory, memory recall, and orientation to time and place.21 Each item on the test is scored as 0 or 1 with the total score varying between 0 and 30. The MMSE utilized in this study was adapted to the Portuguese population.22 In this study, the cut-off points were based on the educational level of the Portuguese population, where cognitive impairment was present if ≤1 points if illiterate, ≤22 if 1-11 years of formal education and ≤27 if more than 11 years of school.\n\nThe Hospital Anxiety and Depression Scale (HADS) helps the diagnosis of anxiety and depression in patients without previous psychiatric history. This instrument excludes symptoms of severe psychiatric disease and physical disease and it is divided into two parts, anxiety and depression, with each sub-section consisting of seven questions. These two parts are classified separately and cover several domains with control of possible confounding factors.23 A total subscale score of eight or more points out of 21 denotes considerable symptoms of anxiety or depression. The scale applied in this study was validated for the Portuguese population.24\n\nThe Brief Symptom Index (BSI) instrument consists of 53 items which the subject must rate how much a certain problem has affected them within the last week. It is a smaller version of the instrument Symptom Checklist-90-Revised (SCL-90-R) and the classification is based on a Likert-type scale (a psychometric scale). An approach to nine symptom dimensions is made (somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism) and three global indices of distress (Global Severity Index, Positive Symptom Distress Index, and Positive Symptom Total. The cutoff point for considering the existence of positive symptoms/pathology is above 1.7.19 An adapted and validated scale aimed at the Portuguese population was utilized.25\n\nTo assess QoL and due to the need for an instrument that would be easily applicable in clinical trials or large-scale epidemiological studies, the World Health Organization (WHO) created the WHO-QoL Bref, which encompasses four domains related to quality of life (physical, psychological, social, and environmental). The score can be calculated in all or each domain, and QoL is better the higher the score.26 An adapted and translated scale was applied to the sample.27,28\n\nData were analyzed using SPSS statistics (IBM SPSS Data Editor Version 25.0 IBM Corp, Armonk, NY) software. Descriptive statistics (median and range for continuous variables, frequency and percentages for categorical variables) and univariate analysis (Mann-Whitney U Test, linear regression, one-way ANOVA and independent sample T-test for continuous data, chi-square and Fisher exact test for categorical data) were utilized, presenting data on the odds ratio (OR) and 95% confidence interval (CI), p≤0.05 was considered significant.\n\nThe study was reviewed and approved by the Ethics Committee of the Instituto Português de Oncologia de Coimbra Francisco Gentil, E.P.E (02/2020), and performed following the ethical standards of the 1964 Declaration of Helsinki,29 as well as its subsequent amendments. Upon inclusion, the study was carefully explained to all patients and an informed consent form was presented and signed by the patients who agreed to participate.\n\n\nResults\n\nA total of 128 patients were evaluated and 91 included (37 patients refused to participate because they did not consider this evaluation necessary). All patients were female, median age was 59.79 years at study inclusion, 49.90 years at breast cancer diagnosis and ECOG-PS was 0 in 62.6% of patients.\n\nRegarding gynecological and obstetric history, menarche was between 10 and 12 years old in 58.3%; 69.2% of patients had used oral contraceptives at some point in their lives; 96.7% of patients had children and 64.8% had their first child before age 30; 75.8% of patients were postmenopausal or under ovarian function suppression at the time of data collection.\n\nA history of psychiatric disorder was present in 16.5%: anxiety was the most frequent disease (7.7%), 16.5% were using psychiatric medication and 6.6% were already followed in a Psychiatry consultation. Regarding habits, 73.6% were non-smokers and 65.9% did not have alcoholic habits.\n\nThe most frequent molecular subtype was Luminal B HER2 negative (47.3%). At diagnosis 60.4% of patients had non-metastatic tumors, 19.8% underwent neoadjuvant chemotherapy, 51.6% underwent surgery with curative intent – more frequently mastectomy with axillary dissection (25.3%), and 34.1% underwent adjuvant chemotherapy. At the time of data collection 26.3% of patients were under first-line of palliative treatment, 51.8% under second-line, and 21.9% under third-line. Treatment consisted in hormonal therapy in 69.19% of patients, chemotherapy in 36.2%, chemotherapy with anti-HER2 therapy in 31.8%, hormonal therapy with cyclin inhibitors 4/6 in 20.8%, hormonal with anti-HER2 therapy in 9.89% and anti-HER2 therapy in 5.49%. Grade 3-4 toxicity had occurred in 32.9% of patients. Patient characteristics can be consulted in Table 1.\n\nMMSE scale application showed that none of the patients had cognitive impairment. HADS scale results showed that 18.7% of the patients scored positively for anxiety and 17.6% for depression. BSI scale application showed that 2.2% of patients surpassed the cut-off of 1.7, presenting positive symptoms. A total of 17 (18.6%) patients fulfilled HADS (n=17) or BSI criteria (n=2) for Psychiatric referral, of these, only 52.9% were consulted by a psychiatrist since the remaining patients refused observation.\n\nThere was a statistically significant relationship between an anxiety subscale score of >8 (HADS) and ovarian function suppression (median 12.40, p<0.001), use of neoadjuvant therapy regardless of the type of treatment (median 7.47, p<0.001), and use of hormonal and anti-HER2 therapy in tsecond-line of palliative treatment (median 7.44, p=0.024).\n\nThe anxiety subscale general score was higher in postmenopausal patients (median 6.53, p=0.002), particularly in patients with ovarian function suppression (median 12.40, p<0.001). It was also higher in patients with stage IV disease at diagnosis (median 6.86, p=0.045), treated with hormonal therapy as first-line (median 6.64, p=0.041), treated with anti-HER2 therapy and chemotherapy as second-line (median 11, p=0.044), and treated with chemotherapy as third-line (median 7.82, p=0.020).\n\nRegarding the depression subscale score >8 of HADS, there was a statistically significant relationship with previous mastectomy with axillary dissection (median 7.96, p=0.022), HER2-negative Luminal B tumors (median 6.52, p=0.020), and grade 3-4 toxicities in the first (median 6.44, p=0.018) and third-line treatments regardless of the type of treatment (median 9.43, p=0.031). The depression subscale general score of HADS was also higher in older patients (median 6.43, p=0.006), postmenopausal patients (median 6.37, p=0.007), and in those treated with chemotherapy as third-line (median 10, p< 0.001).\n\nRegarding BSI score >1.7, there was a statistically significant relationship with moderate alcohol habits (p=0.013). Details concerning the HADS and BSI scores can be consulted in Table 2.\n\nOf the 17 patients with referral criteria for a Psychiatry appointment (17 scored positively on the HADS scale and 2 on the BSI scale), only 9 patients accepted the referral and of these all were diagnosed with some type of psychiatric disorder.\n\nOf the nine patients who accepted referral for psychiatric consultation, 55.55% were diagnosed with dysthymic disorder (F34.1), 33.33% with depression (F33), and 11.11% with adjustment disorder (F43.2). All patients were considered to have indication from treatment with an antidepressant, 44.44% required an association with an anxiolytic, and 22.22% with an antipsychotic.\n\nThe median total score on the WHOQoL-Bref was 92.33 points, the environment domain was the highest with a median score of 80.53, followed by the social relationships domain with 77.89, psychological domain with 77.05, and physical domain with 69.79.\n\nThe better the ECOG-PS the higher the WHOQoL-Bref score, particularly in the physical and social relationships domains (p<0.001). Menopause also seemed to influence physical, psychological and social relationships domains, particularly the physical domain, in which premenopausal women had a higher median scored postmenopausal women (median 79.14 versus 66.81, p<0.001). On the other hand, women who underwent ovarian function suppression scored lower in the psychological domain (median 57.83 versus 74.80 for natural menopause vs 80.94 for surgical menopause, p=0.002). The absence of previous psychiatric history/medication seemed to influence the environmental domain (median 81.58, p=0.002), which was also related to alcoholic habits with abstinent patients scoring higher (median 80.13, p=0.018). Patients with initial stage IV tumors scored lower in all domains, except social relationships (median 78.31, p=0.007). Patients under hormone therapy and cyclin inhibitors 4/6 as second-line treatment scored higher in all domains, particularly the environment domain (median 89.29, p<0.001). Occurrence of grade 3-4 toxicities also seemed to affect scores, particularly the physical domain in patients under first-line treatment (median 61.75, p=0.016), social relationships domain in second-line (median 88,60, p<0.001) and third-line (p=0.009), and environment domain in third-line (median 83.71, p=0.013). Details concerning the scores of WHO-QOL Bref are shown in Table 3.\n\n\nDiscussion\n\nIn this study, 5.49% of our patients were diagnosed with a dysthymic disorder and 3.28% with depression, with the diagnosis of anxiety playing a secondary role in this sample of patients. The prevalence of psychiatric disorder in cancer patients, not specifically breast cancer patients, has been assessed before and it varies between studies, ranging from 13 to 56%.7,10 Our study showed a prevalence closer to the lower percentages reported. On the other hand, the prevalence of adjustment disorders has been assessed as high as 68%, and in our study these disorders played a secondary role (1.09%).7\n\nThe BSI scale positively screened only two of the nine patients (22.2%) referred for Psychiatry appointment, and we postulate that this may be due to the scale's extension, with 53 items, and the patient's exhaustion while responding to it.21,22 Indeed, the fact that BSI scale requires a considered amount of time and concentration might be one of its main drawbacks. Hence, in our study, HADS seemed to be the scale with the best efficacy at screening patients, by identifying 17 patients (18.6%) that could benefit from psychiatric appointment. The fact that this tool has proven to be the most effective in identifying patients is possibly related, among other factors, to its quick applicability.23 All patients who were positively screened by the scales and who were evaluated by a psychiatrist were eventually diagnosed with psychiatric pathology, suggesting a high specificity of this scale, which is in accordance with other studies - For distress (any mental ill health) the HADS-T, HADS-D and HADS-A had a pooled sensitivity and specificity of 72.8%, 80.6%; 75.7%, 66.3% and 65.7%, 71.3%, respectively.30\n\nQoL assessment also proved to be a lengthy process, since it was the reserchers preception that this scale took the longest time both in the response phase by participants and in the interpretation phase by the researchers. Since QoL is such an important measure in oncology, particularly in a palliative setting, this drawback of the WHOQoL-Bref score highlights the importance of developing quicker and simpler scales for use in an outpatient setting. According to our experience, the WHOQoL-Bref may not serve as an effective pillar as a screening tool for psychiatric illness.\n\nWe were also able to demonstrate that the presence of psychiatric pathology was possibly related to several variables related to the characteristics of the tumor and the patient similar to what was described in previous studies.4–6 Thus, after applying the scales, we could determine a few relationships - moderate alcohol habit seems to influence the existence of positive psychiatric symptoms, similarly to what is described in Arias F. et al31; patients who underwent ovarian suppression therapy scored higher on the anxiety subscale, which is contrary to what is shownby Yi HW et al, in which no differences in anxiety score were demonstrated in this subgroup of patients, compared to patients without ovarian suppression therapy32 and patients who underwent mastectomy with axillary dissection demonstrated to score more on the depression subscale, and this is in agreement with other studies, in which it is demonstrated that patients who undergo this type of surgical procedure have a higher prevalence of depression compared to those who do not.33\n\nThe QoL score on the quality-of-life assessment questionnaire, either in totality or in any of the domains, it was more influenced by factors related to advanced disease, which is in agreement with another study - the quality of life decreases substantially in advanced breast cancer.34\n\nWe find it important to note that 28.9% of patients refused to participate in the study and 47% of patients who were offered a psychiatric consultation refused. There are several reasons for this and our study was not designed to explore that, but we postulate that a certain level of prejudice regarding psychiatric disorder may be one of them.\n\nTo our knowledge, this is the first study to evaluate the prevalence of psychiatric disease in patients with metastatic breast cancer from Portugal, and it highlights the importance of educating both health care professionals and patients regarding the spectrum of psychiatric and psychologic disorders, as well as the importance of developping and using effective tools at screening these patients.\n\nOur study has some limitations: the fact that it is a single-center study limits the generalization of our findings, and our sample of patients is heterogenous, since we included patients under different treatments and at different stages of advanced disease. We were also subjected to selection bias by selecting our patients at the outpatient daycare unit where most patients are present for treatment with subcutaneous or intravenous treatments such as ovarian suppression medications and chemotherapy, which translates into a younger sample of patients than expected for patients with breast cancer.\n\nScreening for psychological and psychiatric disorders requires a specific time allocated to the oncology consultation or more time available for patient observation, which may not be possible in all cancer centers and departments. This highlights the importance of screening tools that are simple and quick to apply, such as the HADS scale. On the other hand, the existence of a Psychiatry department with a quick response capacity and patient orientation is necessary in order to guarantee timely and adequate evaluation as well as detection and intervention of relevant psychopathology which may influence patient orientation and response.\n\n\nConclusion/Generalisability\n\nScreening patients with metastatic breast cancer for psychiatric disorders is of the utmost importance. Not all patients can and need to be observed in a psychiatric appointment; hence, providing medical and radiation oncology teams with simple and quick to implement tools to screen their patients can lead to referral for consultation and subsequent diagnosis and treatment of psychiatric disease at an earlier stage. In our study, HADS proved to be particularly helpful at this task, since it was quick to apply and showed a good specificity for psychiatric disease.\n\n\nData availability\n\nFigshare: Database.xlsx, https://doi.org/10.6084/m9.figshare.18364970.v1.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nAn earlier version of this article can be found on Research Square (DOI: 10.21203/rs.3.rs-946803/v1)\n\n\nReferences\n\nLopez AD, Murray CC: The global burden of disease, 1990–2020. Nat. Med. 1998; 4(11): 1241–1243. PubMed Abstract | Publisher Full Text\n\nAnuk D, Özkan M, Kizir A, et al.: The characteristics and risk factors for common psychiatric disorders in patients with cancer seeking help for mental health. BMC Psychiatry. 2019; 19(1): 1–11. Publisher Full Text\n\nMcGuire S: World cancer report 2014. Geneva, Switzerland: World Health Organization, international agency for research on cancer, WHO Press; 2016; 7(2): 418–419. 2015. Advances in nutrition.\n\nZabora J, BrintzenhofeSzoc K, Curbow B, et al.: The prevalence of psychological distress by cancer site. Psycho-Oncology: Journal of the Psychological, Social and Behavioral Dimensions of. Cancer. 2001; 10(1): 19–28. Publisher Full Text\n\nBultz BD, Holland JC: Emotional distress in patients with cancer: the sixth vital sign. Commun. Oncol. 2006; 3(3): 311–314. Publisher Full Text\n\nHolland JC, Andersen B, Breitbart WS, et al.: Distress management. J. Natl. Compr. Cancer Netw. 2010; 8(4): 448–485. Publisher Full Text\n\nDerogatis LR, Morrow GR, Fetting J, et al.: The prevalence of psychiatric disorders among cancer patients. JAMA. 1983; 249(6): 751–757. Publisher Full Text\n\nChahl P, Bond A: ‘I’m sorry but you've got cancer: the role of psycho-oncology. British Journal of Hospital Medicine (2005). 2009; 70(9): 514–517. PubMed Abstract | Publisher Full Text\n\nBreitbart W: Identifying patients at risk for, and treatment of major psychiatric complications of cancer. Support. Care Cancer. 1995; 3(1): 45–60. PubMed Abstract | Publisher Full Text\n\nLevine PM, Silberfarb PM, Lipowski ZJ: Mental disorders in cancer patients. A study of 100 psychiatric referrals. Cancer. 1978; 42(3): 1385–1391. PubMed Abstract | Publisher Full Text\n\nTada Y, Matsubara M, Kawada S, et al.: Psychiatric disorders in cancer patients at a university hospital in Japan: descriptive analysis of 765 psychiatric referrals. Jpn. J. Clin. Oncol. 2012; 42(3): 183–188. PubMed Abstract | Publisher Full Text\n\nMassie J: Overview of normal reactions and prevalence of psychiatric disorders. Handbook of psycho-oncology. 1989.\n\nLoberiza FR Jr, Rizzo JD, Bredeson CN, et al.: Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases. J. Clin. Oncol. 2002; 20(8): 2118–2126. PubMed Abstract | Publisher Full Text\n\nValdimarsdottir U, Helgason ÁR, Fürst CJ, et al.: The unrecognized cost of cancer patients' unrelieved symptoms: a nationwide follow-up of their surviving partners. Br. J. Cancer. 2002; 86(10): 1540–1545. PubMed Abstract | Publisher Full Text\n\nKurtz ME, Kurtz JC, Given CW, et al.: Relationship of caregiver reactions and depression to cancer patients' symptoms, functional states and depression—a longitudinal view. Soc. Sci. Med. 1995; 40(6): 837–846. PubMed Abstract | Publisher Full Text\n\nKissane DW, Grabsch B, Love A, et al.: Psychiatric disorder in women with early-stage and advanced breast cancer: a comparative analysis. Aust. N. Z. J. Psychiatry. 2004; 38(5): 320–326. PubMed Abstract | Publisher Full Text\n\nRishi P, Rishi E, Maitray A, et al.: Hospital anxiety and depression scale assessment of 100 patients before and after using low vision care: A prospective study in a tertiary eye-care setting. Indian J. Ophthalmol. 2017; 65(11): 1203–1208. PubMed Abstract | Publisher Full Text\n\nCanavarro MCCDSP: Relações Afectivas ao Longo do Ciclo de Vida e Saúde Mental (Doctoral dissertation).1997.\n\nDerogatis LR, Melisaratos N: The brief symptom inventory: an introductory report. Psychol. Med. 1983; 13(3): 595–605. PubMed Abstract | Publisher Full Text\n\nSantana I, Duro D, Lemos R, et al.: Mini-Mental State Examination: Screening and diagnosis of cognitive decline, using new normative data. Acta Medica Port. 2016; 29(4): 240–248. PubMed Abstract | Publisher Full Text\n\nFolstein MF, Folstein SE, McHugh PR: “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 1975; 12(3): 189–198. Publisher Full Text\n\nGuerreiro M, Silva AP, Botelho M, et al.: Adaptação a população portuguesa da tradução do Mini Mental State Examination (MMSE). Revista Portuguesa de Neurologia. 1994; 1: 9.\n\nBjelland I, Dahl AA, Haug TT, et al.: The validity of the Hospital Anxiety and Depression Scale: an updated literature review. J. Psychosom. Res. 2002; 52(2): 69–77. Publisher Full Text\n\nPais-Ribeiro J, Silva I, Ferreira T, et al.: Validation study of a Portuguese version of the Hospital Anxiety and Depression Scale. Psychol. Health Med. 2007; 12: 225–237. PubMed Abstract | Publisher Full Text\n\nCanavarro MC: Inventário de Sintomas Psicopatológicos: BSI. Simões MR, Gonçalves M, Almeida LS, editors. Testes e provas psicológicas em Portugal. Braga: SHO/APPORT; 1999; (vol. II. , pp. 87–109).\n\nSkevington SM, Lotfy M, O'Connell KA: The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual. Life Res. 2004; 13(2): 299–310. PubMed Abstract | Publisher Full Text\n\nCanavarro MC, Simões MR, Vaz Serra A, et al.: Instrumento de avaliação da qualidade de vida da Organização Mundial de Saúde: WHOQOL-Bref. Simões M, Machado C, Gonçalves M, et al., editors. Avaliação psicológica: Instrumentos validados para a população portuguesa. Coimbra: Quarteto Editora; 2007; (Vol. III. , pp. 77–100).\n\nCanavarro MC, Vaz Serra A, Pereira M, et al.: WHOQOL disponível para Portugal: Desenvolvimento dos instrumentos de avaliação da qualidade de vida da Organização Mundial de Saúde (WHOQOL-100 e WHOQOL-BREF). Canavarro MC, Vaz Serra A, editors. Qualidade de vida e saúde: Uma abordagem na perspectiva da Organização Mundial de Saúde. Lisboa: Fundação Calouste Gulbenkian; 2010; (pp. 171–190).\n\nRickham PP: Human Experimentatio. Code of ethics of the world medical association of Helsinki. Br. Med. J. 1964; 2(5402): 177. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMitchell AJ, Meader N, Symonds P: Diagnostic validity of the Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-analysis. J. Affect. Disord. 2010; 126(3): 335–348. PubMed Abstract | Publisher Full Text\n\nArias F, Szerman N, Vega P, et al.: Alcohol abuse or dependence and other psychiatric disorders. Madrid study on the prevalence of dual pathology. Ment. Health Subst. Use. 2013; 6(4): 339–350. Publisher Full Text\n\nYi HW, Nam SJ, Kim SW, et al.: Abstract P1-11-01: Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients.2016.\n\nKim MS, Kim SY, Kim JH, et al.: Depression in breast cancer patients who have undergone mastectomy: a national cohort study. PLoS One. 2017; 12(4): e0175395. PubMed Abstract | Publisher Full Text\n\nGrabsch B, Clarke DM, Love A, et al.: Psychological morbidity and quality of life in women with advanced breast cancer: a cross-sectional survey. Palliat. Support. Care. 2006; 4(1): 47–56. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "174462",
"date": "23 Feb 2024",
"name": "Jheelam Biswas",
"expertise": [
"Reviewer Expertise Palliative 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\nCongratulations on your hard work. It is an important piece of work regarding the psychiatric status of Portuguese breast cancer patients. However, I have some observations: 1. Table 1: You have only stated the number of depression and anxiety. I think HADS has three categories for depression and anxiety. State them separately too. 2. Table 2: is very complex. Please clarify which statistical tests are used for which result in the footnote. Also, I recommend elaborating the table with more detailed results. 3. Discussion: 1st two paragraphs are mostly repetitions of your result. Try to minimize the repetitions and add more comparisons with other literature. You have only mentioned the HADS scores in the 2nd paragraph.Try to categorize the scores according to the given criteria in the tool (eg. moderate or severe depression). 4. 3rd paragraph of the discussion can be moved after the 4th paragraph. 5. In the 5th paragraph, mention the name/place of the study you have compared the QOL with (reference no 34) in the text (eg. a study conducted in Australia).\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": "11181",
"date": "13 Apr 2024",
"name": "Raquel Basto",
"role": "Author Response",
"response": "Table 1 refers to the characteristics of the sample - not exactly HADS. Table 2 - Descriptive statistics (median and range for continuous variables, frequency and percentages for categorical variables) and univariate analysis (Mann-Whitney U Test, linear regression, one-way ANOVA and independent sample T-test for continuous data, chi-square and Fisher exact test for categorical data) were utilized, presenting data on the odds ratio (OR) and 95% confidence interval (CI), p≤0.05 was considered significant."
}
]
},
{
"id": "166065",
"date": "14 May 2024",
"name": "Andreas Stengel",
"expertise": [
"Reviewer Expertise psychosomatic",
"psychooncology"
],
"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 the paper ‘Screening patients with metastatic breast cancer for psychiatric disease: a cross sectional study’ the authors report on psycho-oncological screening results in a sample of patients with metastatic breast cancer. Several points should be addressed.\nMajor:\nThe sample size of screened patients is very small and should be largely increased (> 10-fold). Otherwise the study is likely underpowered and no stratification is possible (only 9 patients have a psychiatric diagnosis).\n\nOn these 9 patients right now one cannot comment on risk factors (see point 1).\n\nThe study rational remains unclear.\n\nIt is not clear why the authors distinguish between \"psychological and psychiatric disorders\".\n\nWould there then be a different kind of psycho-oncological treatment?\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?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-73
|
https://f1000research.com/articles/10-776/v1
|
09 Aug 21
|
{
"type": "Research Article",
"title": "The Correlation between Enjoying Fictional Narratives and Empathy in Japanese Hikikomori",
"authors": [
"Francesco Panto",
"Tamaki Saito",
"Nobuaki Morita",
"Yasukazu Ogai",
"Tamaki Saito",
"Nobuaki Morita",
"Yasukazu Ogai"
],
"abstract": "Background: Hikikomori is a Japanese social withdrawal phenomenon which, in recent years, is spreading in western developed countries as well. Spending a lot of time secluded indoors, watching and playing with fictional narratives may be relatively common for Hikikomori people and may represent a protective factor for their psychological well-being.\n\nMethod: We evaluated the role of enjoying fictional narratives on empathy, relaxation, depression, and anxiety in people with Hikikomori experience, in relation to their daily consumption of fictional narratives and their emotional transportation toward fictional narratives. Hikikomori from one psychiatric clinic and three different support facilities were enrolled in this study. Multidimensional empathy scale, CES-D, STAI questionnaire, and relaxation inventory self-report scale were used as outcome measures.\n\nResults: We found a significant correlation between empathy and emotional transportation toward fictional narratives and between relaxation during watching and reading fictional narratives and consumption frequency of fictional narratives. We failed, however, to find any significant correlation with depression and anxiety.\n\nConclusions: These findings suggest a possible correlation between fiction and empathy/relaxation response; however, any causal relationship is not proven, consequently we deem that further investigations with a larger sample size are required for a better understanding.",
"keywords": [
"Hikikomori",
"Social withdrawal",
"Emotional transportation",
"Empathy",
"narrative therapy"
],
"content": "Introduction\n\nHikikomori could be defined as a socio-medical condition originally manifested in Japan during the end of the twentieth century. The core feature of Hikikomori is considered to be a withdrawal with various degrees from social life. Hikikomori people spend most of the day confined indoors. Avoidance of social situations and social relationships, and functional impairment of social interactions are usually present. According to the Japanese Ministry of Health, Labor and Welfare (Saito, 2010), Hikikomori is defined as “a situation where a person without psychosis is withdrawn into his/her home for more than six months and does not participate in society such as attending school and/or work”. Lifetime prevalence of Hikikomori in Japan is said to be 1.2% (Koyama et al., 2010). A Japanese cabinet report has estimated the actual number of Hikikomori in Japan as around 540,000 (Tajan et al., 2017), yet this estimation varies a lot among experts. For the general public staying indoors continuously is classically considered as a necessary feature of being Hikikomori. However, according to Japanese experts (Saito, 1998), the Hikikomori condition refers to a withdrawal from social situations, activity, and relationships with others without necessarily being physically restrained indoors. In Japan a large number of Hikikomori are still considered as such even if they visit hospitals, psychiatric clinics, employment support facilities, or even when they have an employment (Otaya, 2015). Originally considered as a cultural-bound syndrome profoundly embedded with cultural peculiarities of Japanese society, nowadays Hikikomori is reported in different economically developed countries.\n\nKato et al. (2011) found that among 124 mental health professionals from eight countries, Hikikomori-like phenomena were reported, furthermore differences among countries were not significant, suggesting that cultural etiology could not be the only cause behind the phenomenon (Kato et al., 2011). Hikikomori case studies have been conducted from several countries outside Japan including, Spain, Oman, the United States, Canada, Italy, the United Kingdom, France, Taiwan, and South Korea (Lee et al., 2015; Malagón-Amor et al., 2014; Sakamoto et al., 2005). For the etiology of Hikikomori there are variegated and yet contradicting points of views from experts. Hikikomori is not classically considered a psychiatric diagnosis. Some cases of Hikikomori meet the criteria of existing disorders in the DSM V (or ICD- 10), yet a consistent subset of cases does not meet the criteria of any existing psychiatric disorders, motivating some researchers to propose Hikikomori as a cultural-bound syndrome (Teo & Gaw, 2010). Among western sociologists there are researchers who suggest that Hikikomori do not have inherent psychopathology, consequently, it can represent a transient phenomenon caused only by social factors (Furlong, 2008). Even if we fail to ascribe the Hikikomori phenomenon to a precise and univocal DSM V or ICD-10 diagnosis, it is still undeniable that people suffering from Hikikomori battle with a variegated cluster of psychiatric symptoms that results in impairing their daily activities. According to research by Kondo (Kondo et al., 2013) in about 148 Hikikomori patients out of a 337 total who presented to medical institutions to be treated, a medical diagnosis was made according to DSM-IV-TR criteria.\n\nSchizophrenia, anxiety disorder, mood disorder, adjustment disorder, personality disorder (including six with avoidant personality disorder, schizoid personality disorder, obsessive-compulsive personality disorder) were commonly found (Suwa & Suzuki, 2013). Even if the Hikikomori phenomenon is not a disease “per se”, a prolonged social withdrawal could trigger psychiatric symptoms. Saito (2009) described the Hikikomori personality as characterized by low self-esteem and a tendency to feel anxious and nervous in front of other people. In regard to the correlation between Hikikomori and internet addiction, there is not univocal consensus, as many researchers seem to point to internet use and online communication as a predisposing factor leading to social withdrawal (Taylor, 2006). Internet addiction and Hikikomori could also function as a comorbidity of the other. According to one study conducted In South Korea, 56% of Hikikomori are at risk of internet addiction, using the internet as their only way of communicating with the world (Chan & Lo, 2014). On the other hand, it has been suggested that internet usage, being the preferred communication and social tool used by Hikikomori, could be paradoxically beneficial for a Hikikomori’s quality of life (Lee et al., 2013). It could be a potential way to interact with medical professionals or even represent a means to attend school. In this regard it is worth mentioning that in Japan a rising popular online school, called Nko (Nkoutougakkou) allows futoko (students with school refusal) and Hikikomori individuals to attend school directly from their rooms, becoming a precious tool that links them to a real community. In Japan, fictional narrative (mostly in the form of Anime and Manga) consumption behavior is classically related to the term Otaku. The term Otaku refers to “people who are interested in a specific genre or object, and are extraordinarily knowledgeable about it, but are lacking in social common sense” (Kam, 2013). Generally speaking, in Japan, the word Otaku is used to speak about people who have a high consumption of anime or manga productions and related goods. The relationships between Hikikomori and Otaku is not quite clear yet. Some Japanese experts have suggested that Hikikomori individuals often refuse to be labeled as Otaku for the social stigma linked to the word (Saito, 2009) Nevertheless, Saito (2009) also states that young otaku(s) in Japan tend to be bullied at school due to the presence of a “school caste system” that judges otaku students incapable of meaningful communication with peers. So, in the end younger otaku(s) tend to become Hikikomori in their adult life, developing an inferiority complex toward others. For these reasons we can assume that a part of Hikikomori population enjoys fictional narratives in their daily life. Asking Hikikomori individuals if they habitually use fictional narratives in their daily life and assessing the psychological effects of this activity, with this study we want to make an attempt in understanding this relationship. If a beneficial relationship is established, in the future we could use a form of remote narrative therapy to help Hikikomori. This therapy would be based on an activity which they already enjoy on a daily basis. This new narrative therapy approach could represent a tool of intervention in a population reluctant to get in touch with mental health facilities.\n\n“Fictional narratives” is a term used to classify activities that comprise enjoying a production which does not include actual factual information, like watching movies or anime, reading novels, or playing video games. They are fictional because they are not based on real facts or stories (or at least not entirely). (Busselle & Bilandzic, 2008). Enjoying fictional narratives is something everybody has experienced at least once in their lifetime and it has been suggested to benefit the personal insight of individuals, giving opportunities for self- discovery and self-insight (Green & Brock, 2002; Oatley, 1999; Oatley, 2002; Pelowski & Akiba, 2011). The mechanism through which this is deemed to be possible has been postulated by Green & Brock in their transportation-imagery model or emotional transportation theory (Green & Brock, 2002), and is thought to be possible through emotional transportation. Emotional transportation is defined as being emotionally involved with fictional characters of a fictional story. The spectator of a fictional narrative production, if certain personal and environmental preconditions are present, will fall into a state of emotional detachment and be transported in the world of the story (Van Laer et al., 2014). This process, described in the transportation theory, may be mediated, according to Van Lear, by the empathy the spectator grows toward the story characters and the vivid imagination of the plot occurring in the mind of the spectator (Coplan, 2004). The process implicated in the transportation imagery model by Green & Brock could lead to different effects on the psyche of the spectator. One could be the enhancing of empathy toward other people. It has been suggested that people who enjoy a large quantity of fictional narrative productions become more empathetic towards other people (Mar et al., 2006). One possible interpretation that has been raised is that, for the mind of the spectator, fiction functions as a simulation of human and social interactions, therefore narrative may function as an indirect learning experience (Argo et al., 2008). In contrast, some researchers suggest that a possible explanation for fiction positively associated with empathy is that more empathetic people tend to enjoy more fiction in the first place (Bal & Veltkamp, 2013). The debate whether fiction influences empathy or not is still ongoing, but Bal & Veltkamp (2013) with an experimental approach demonstrated an undeniable influence of fiction compared to non-fiction to the empathy of the individual, but only when low or high emotional transportation into the specific story enjoyed occurred (Busselle & Bilandzic, 2009). The mediating role of emotional transportation in influencing empathy skills may be the main candidate in predicting empathy (Busselle & Bilandzic, 2009; Gerrig, 1993). Aside from emotional influence, the narrative transportation model predicts that narratives can induce a cognitive persuasion on the spectator, which is strong and long-lasting (Coplan, 2004). In other words, fictional narratives may trigger a cognitive transformation experience (Green & Brock, 2000; Phillips & Mcquarrie, 2010). Further investigations on this field lead to the distinction between analytical and narrative persuasion (Petty & Cacioppo, 1986). Compared to analytical persuasion of factual stories, narrative persuasion is not overtly persuasive, is not inherently critical and does not involve scrutiny, characteristics that allow persuasion to be more effective and long-lasting (Appel & Richter, 2007; Locke, 1987; Slater, 2002). The narrative persuasion evoked by fictional narratives could be linked to the Bandura Social Learning theory (Evans et al., 1970). In this case, observation and subsequent behavioral imitation stems not from people in actual society but from fictional narrative characters.\n\nAccording to a fact-finding investigation about Hikikomori conducted by the Japanese Ministry of Health, Labour and Welfare, in 2010, concerning activities engaged in indoors, Hikikomori individuals engaged more in the reading of books, playing video-games and using internet compared to healthy individuals (Japanese Ministry of Health, Labour and Welfare, 2010). Yet, actually there is no data regarding Hikikomori engaging in fictional narratives in their daily lives more than healthy individuals. The rationale of this investigation is based on the hypothesis that Hikikomori individuals that engage more often in fictional narratives, or who are more easily emotionally transported to a story tend to be more empathetic at the same level of social impairment. We want also to verify if Hikikomori individuals, who engage in fictional narratives more often or have a higher level of emotional transportation, have accordingly lower levels of the anxiety and depression associated with their condition. According to previous researches, there are few but significant findings of the relationship between empathy and fictional narrative consumption. However, to the authors’ knowledge, there are no studies that try to estimate if the consumption of fictional narratives may or may not enact as a protective factor against depression or anxiety in socially impaired individuals. If a beneficial correlation is established it could be worth trying to develop a method of intervention using fictional narratives (anime, games) to support Japanese socially impaired individuals.\n\n\nMethods\n\nDue to the natural reluctance of actively secluded Hikikomori individuals to seek medical attention, we enrolled in this study Hikikomori who had already got in touch with medical facilities (psychiatric clinics) or non-profit support facilities providing Hikikomori individuals - self-help groups or employment support. For this reason, Hikikomori enrolled in this study are considered “people who experienced Hikikomori phenomenon” and not people who were actively secluded. Inclusion criteria were (a) belonging to a support facility for Hikikomori or be treated for Hikikomori as an outpatient or a daycare patient in a psychiatric clinic or hospital. (b) being over 18 years old. (c) being Japanese and (d) having experienced Hikikomori condition for over six months in the past (this study doesn’t not include actively secluded Hikikomori). Participants were excluded if they presented (a) other psychiatric symptoms aside from social seclusion and impairment (b) psychotic symptoms.\n\nThe study received ethical approval from the Bio-Ethical Committee of Tsukuba University (ethical approval number 1247). We conducted a cross- sectional questionnaire survey from January 2018 to December 2018 in four different facilities. Three of them were non- profit support organizations and one was a psychiatric clinic (in this case we recruited patients in the daycare facility and in the outpatient care as well), all located in the Kanto area, Japan. The recruitment procedure consisted of a periodic explanation by the authors of the research purpose and research protocol to Hikikomori individuals attending the support facilities and psychiatric clinic. Hikikomori individuals interested in the questionnaire were instructed to contact the facility staff afterward. After an evaluation of the patient eligibility by the authors the questionnaires were distributed to participants. The participants could either or compile the questionnaire directly right after the distribution or could bring it home and return afterward to the facilities staff. After collection, participation reward (a 500yen prepaid card) was granted to Hikikomori individuals who answered the questionnaire.\n\n\nMeasures\n\nThe Center for Epidemiologic Studies Depression Scale, Japanese version (CES-D). The CES-D is considered one of the gold-standard measures for depression. It a brief self-report 20-item measure that asks participants to rate how often over the past week they experienced symptoms associated with depression (Lewinsohn et al., 1997). Response options range from 0 to 3 for each item (0 = Rarely or None of the Time, 1=Some or Little of the Time, 2=Moderately or Much of the time, 3 = Most or Almost All the Time). Scores range from 0 to 60. The cutoff score for clinical depression is 16 or greater. We decided to use the CES-D to assess any difference in depressive symptoms between Hikikomori individuals with a high and low rate of fictional narrative consumption and with high and low scores in emotional transportation.\n\nThe State-Trait Anxiety Inventory (Spielberger, 1983). The State-Trait Anxiety Inventory (STAI) is a scale used to measure trait anxiety. It is generally used in clinical settings from physicians and clinical psychologists to diagnose anxiety. In this study, we implemented the 20 items version. All items are rated on a four-point-scale (e.g., from “Almost Never” to “Almost Always”). Higher scores indicate greater anxiety. This scale is considered one of the most valid and reliable instruments to assess clinical anxiety (Suzuki & Kino, 2008).\n\nMultidimensional Empathy Scale. Multidimensional Empathy Scale (MES)is a Japanese 24-item self-report measure of 5 dimensions of empathy, for distinctively assessing self/other- orientation of either cognitive or emotional components. The five dimensions are 1) Other-Oriented Emotional Reactivity, 2) Self-Oriented Emotional Reactivity, 3) Emotional Susceptibility, 4) Perspective Taking, and 5) Fantasy. (the internal consistency indexes for every sub scale were.71 .60 .78 .69 .70). A series of validation studies were made by authors to test the validity of the tool and each of the five sub-scales demonstrated a predictable pattern of relationships with existing scales like Interpersonal reactivity Index IRI or Questionnaire Measure of Emotional empathy QMEE (Mehrabian & Epstein, 1972).\n\nShort-form self-report measure to assess relaxation effect (S-MARE), (Sakakibara et al., 2014). S-MARE is a relatively new self-report tool to assess relaxation effect based on the Relaxation Inventory (Crist et al., 1989). The item consists of three sub scales (a) physiological tension (b) psychological relaxation (c) anxiety. For each sub scale the Cronbach’s coefficient was .93, .94 and .85. S-Mare scores were significantly correlated with the Emotional Relaxation Scale (Tokuda, 2011) (r=.446) and with State Anxiety (r= -.531) (N=172). The validity tests suggested that S-MARE has reliability and validity when correlating with cardiac parasympathetic tone, which is the physiological reaction to a relaxation stimulus. This suggests that S-MARE is a valid measure when measuring relaxation effects. Normally the assessment of relaxation effect occurs after the exposure to a relaxation stimulus evoked by a relaxation technique. For this study, we ask the participants to recall the relaxation state they usually experience while they are enjoying fictional narratives and to answer accordingly.\n\nNarrative Transportation Scale (NTS- J). Japanese version of the scale (Osanai & Kusumi, 2016). NTS-J consists of 12 items and is a seven-point scale (from 1=not fitting at all to 7=fitting perfectly). Transportation into narratives is considered a mechanism by which narratives can affect beliefs. The elements included in the transportation experience are imagery, affect, and attentional focus. The Narrative Transportation Scale (NTS-J) was developed firstly by Green & Brock (2000). A shorter version of the same scale was developed by Appel et al. (2015). According to Green and Brock transportation is associated with story-consistent beliefs, meaning that highly transported participants had beliefs more consistent with the story and showed a more positive evaluation of characters. Although causality is not established, the persuasion effects of narratives are broadly demonstrated, meaning that highly transported individuals changed their real-world beliefs in response to experiences in a fictional world (Osanai & Kusumi, 2016). Japanese confirmatory studies showed the reliability of the scale and the correlation in measuring imaginative involvement and literary response. (Bal et al., 2011) Osanai & Kusumi's scale required the narrative task \"Kin no Wa\" and \"Chiyogami no Haru\" to the respondents. For this study, we instructed the participants not to limit the response to a single fictional production but to answer accordingly to their habitual emotional response to fictional narratives.\n\nIn this study, we decided to set as a predictor measure “habitual consumption of fictional narratives”. We asked if participants had or did not have habitual consumption of fictional narrative productions (movies, anime, manga, novels, drama, or games). We asked if they enjoy fictional narratives “habitually”, “from time to time “and “nothing at all”. For the data analysis, we decided to set two groups. One that comprised only participants with habitual consumption of fictional narratives, the other which included participants who enjoy fictional narratives from time to times and participants who don’t enjoy fictional narratives completely.\n\nHikikomori status evaluation. In order to make an evaluation about the participants’ Hikikomori status we employed a few questions extracted from the “Hikikomori status evaluation chart” implemented by Japan's Ministry of Health, Labour and Welfare, currently used by Japanese psychiatrists (Saito, 2010). Specifically, we asked about the age of onset of Hikikomori phenomenon, the perceived reason linked to the Hikikomori behavior, the number of friends, the experience of being bullying or bullying perpetrating behavior, and the use of internet and TV in daily life.\n\n\nData analysis\n\nTo test the Hypothesis that Hikikomori participants with high fictional narrative consumption rates and Hikikomori participants with low fictional narrative consumption rates were associated with the statistically significantly different mean of scores in the outcomes variables, an independent samples t-test was performed. To test the hypothesis that higher narrative transportation skills or high fictional narrative consumption rates were positively correlated with higher empathy and relaxation, and negatively correlated with anxiety or depression we performed a Pearson correlation test. Afterward, for statistically significant results, multiple regression analysis was performed. The level of statistical significance was set at p<.05. All data analysis was performed using SPSS v. 25 (IBM SPSS Statistics, RRID:SCR_019096).\n\n\nResults\n\nA total of 270 questionnaires were distributed, 84 responses were collected, 4 were excluded from the analysis due to extensive missing values. The remaining 80 were suitable for the analysis. To deal with the remaining amount of missing values, an Expectation Maximization algorithm was used for missing data analysis. A flow chart of the data collection process is shown in Figure 1. The average age of participants (n=80) was 36 (SD 8.6). The period in which they started Hikikomori behavior, the reason they started to actively recluse themselves, the presence or absence of bullying experience, and the number of friends are reported in Table 1. Regarding fictional narrative consumption behavior, the participants’ tendencies are shown in Table 2. We also asked the main reason why they enjoy fictional narratives when they do and the positive emotions elicited by consumption behavior as well as if they experience a decrease in negative emotions during consumption behavior or not, Table 2. To test the hypothesis of a correlation between fiction-consumption-related behavior (emotional transportation and fiction consumption rate) and the dependent variables, a Pearson correlation analysis was conducted. There was a positive correlation between emotional transportation and empathy, r = .498, p = < .001, n = 80. Also, there was a positive correlation between fiction consumption rate and relaxation, r = .280, p = < .005, n = 80, Table 3. An independent-samples t-test was conducted to compare relaxation, empathy, depression, and anxiety levels in Hikikomori with habitual consumption of fictional narratives and Hikikomori without habitual consumption of fictional narratives. There was a significant difference in the scores for habitual consumption (M=53.0, SD=12.4) and non-habitual consumption (M=46.3, SD=8.7) only for relaxation, Table 4. When we compared the level of relaxation between Hikikomori with habitual consumption and no habitual consumption, there was a statistically significant difference between groups as determined by one-way ANOVA (F (2,77) = 3.534, p = .034), Table 5. A multiple regression was carried out to investigate whether emotional transportation and fiction consumption rate could significantly predict participants ‘empathy. The results of the regression indicated that the model explained 23.2% of the variance and that the model was a significant predictor of empathy, F (2,77) = 12.94, p<.01. While emotional transportation contributed significantly to the model (B = .551, p=.000), fiction consumption rate did not (B = -1.41, p=.539), Table 6. For relaxation, the results of the regression indicated that the model explained 5.5% of the variance and that the model was a significant predictor of relaxation, F (2,77) = 3.30, p = 0.042. While fiction consumption rate contributed significantly to the model (B = 6.61, p=0.14), emotional transportation rate did not (B = -0.26, p=.84), Table 6.\n\n*p< .05. **p< .01\n\n*p< .05. **p< .01\n\nNote. Empathy R2= .232. Relaxation R2= .05\n\n\nDiscussion\n\nThis study wanted to explore the connection between empathy relaxation, depression, anxiety, and fictional narrative consumption behavior by Hikikomori Individuals in Japan in order to introduce a new form of narrative therapy for Hikikomori individuals. Due to the lack of data regarding firstly, the influence of habitual consumption of fictional narratives on empathy relaxation, depression anxiety in the general population, moreover in Hikikomori individuals, the outcome setting was mainly exploratory. According to the results pertinent to the outcomes, t-test results have shown a statistically significant difference only for relaxation response in regard to fictional narrative consumption behavior. This could suggest that while consuming fictional narratives, Hikikomori individuals with habitual fictional narratives consumption behavior tend to have a higher relaxation response. For the correlation analysis and the multiple regression analysis conducted using transportation as a continuous variable predicting empathy, we obtained a pattern of results consistent with previous research that showed a correlation between emotional transportation and empathy. Although correlation doesn’t mean causality, in previous research measuring the effects of emotional transportation on fiction and nonfiction readers, it was shown that empathy was influenced only for fiction readers and not for nonfiction, suggesting the validity of emotional transportation theory (Busselle & Bilandzic, 2009). According to the transportation theory and its further developments, in order to change as a consequence of enjoying fictional narratives, the individual has to be emotionally transported, otherwise distraction from the story and consequently, disengagement from the story will occur (Goldstein, 2009; Mar et al., 2009). Goldstein explains further the relationship existing between fiction and empathy. Compared to factual information, fiction is mainly oriented at eliciting emotions. For the spectators, while they are engaging in the characters emotions, the realistic aspect of the story loses its importance and does not act as a hindrance to experiencing characters emotions. On the contrary fictionality of the story could constitute a safe arena for the spectator, protecting from defense mechanisms while allowing the spectator to experience both his and the characters emotions (Eisenberg & Miller, 1987; Goldstein, 2009; Grant, 2008; Grant & Berry, 2011; Stocks et al., 2008). Finding a way to enhance empathy toward others could be meaningful from a psychological and social point of view especially for socially impaired individuals like Hikikomori. By promoting social behavior, empathy is considered to be a pro-social factor. Empathy is also considered to be related to individual creativity and cooperative behavior in the workplace (Dumtrache, 2014; Stocks et al., 2008). If it is true that empathy fosters social behavior, the other way around is also possible, that social contact is essential to maintain empathy skills. According to the social support theory (O’Reilly, 1988), social networks providing emotional concern (love, empathy, liking), instrumental aid, information, and appraisal, are regarded as a basic requirement for existence (Langford et al., 1997). Hikikomori lacking healthy contacts with social networks could exist in a situation in which empathy skills are not promoted or maintained by exchanges with other individuals. In this light, if in future studies causality will be proven, the enhancing of empathy related to consumption of fictional narratives could be meaningful in helping them not to weaken interpersonal skills during social isolation. Aside from empathy, T-test, Pearson correlation and Multi-regression analysis confirmed a relation between the habitual consumption of fictional narratives and relaxation effect. The relaxation effect measured in this study was linked to the physiological and psychological relaxation experienced during consumption of fictional narratives, as we instructed the participants to refer to their state during fictional narrative experiences. According to previous studies, the relaxation effect is correlated with emotional relaxation, physiological tension, and state anxiety. Hikikomori individuals who habitually enjoy fictional narratives or have higher emotional transportation skills tend to be more relaxed while watching a movie or reading a book. Even if the causality of this relationship is not proven and no correlation between predictor variables and anxiety and depression was found in this study, we can surely give some possible interpretations of the relaxation effect. It could be that people with high emotional transportation or fictional narrative consumption habits, have less risk of becoming detached, are more able to immerse themselves in the story and this could act as a protective factor against physiological and emotional tension. For Hikikomori individuals this could be particularly meaningful, given that the comorbidity with anxiety is very common. In this regard, we assessed anxiety with STAI in our study, and we found a mean score for anxiety that was relatively high and above the clinical threshold. The effect of fictional narratives on anxiety symptoms and emotional tension, even if the literature is quite limited, is not an unheard-of topic. In 2014 a study tested the effects of cinema therapy on diminishing anxiety in young people. Compared to a control group, participants who took cinema therapy sessions showed a lower score on the Hamilton anxiety rating scale. This suggests that Cinema Therapy could have a role in decreasing anxiety in individuals with high levels of stress and anxiety (Dumtrache, 2014). Furthermore, another study examined the effects of watching a movie on a family member’s anxiety level during their relatives’ surgery, assessing anxiety with STAI. It was found that after watching a movie the level of anxiety was significantly reduced in people already in an anxious state due to their relative’s surgery (Mojdeh et al., 2013). This suggested a possible protective role of fictional narratives towards anxiety and emotional tension. Johnson (2012) conducted a study demonstrating that engaging in a fictional story fosters not only empathy but also prosocial behavior. Dunbar et al. (2016) proved that emotional arousal when watching drama increases pain thresholds and social bonding. These pro-social behavioral effects could be extremely useful for socially impaired Hikikomori(s). However, another possible explanation for socially impaired people enjoying fiction narratives, could be that people with more depression and anxiety symptoms will interpret various events negatively and ruminate them repeatedly. In other words, lower depression and anxiety or higher relaxation predicting a tendency in enjoying Fictional Narratives is a possible convincing hypothesis. Also, Saito (2020) points out how Hikikomori in their middle age tend to hide their interest in entertainment because of a sense of guilt regarding recreational activities. Finally, with regard to depression and anxiety, no statistically significant result was observed, however a negative correlation between Anxiety, Depression, and Relaxation was observed. With this study, with its relatively small sample size, low coefficients results, and a cross-sectional nature, we couldn’t draw any conclusive evidence about the psychological effects of fictional narrative consumption behavior, but the data suggest a possible correlation of fictional narrative consumption behavior with relaxation and empathy.\n\n\nStudy limitations\n\nThis study incorporated several limitations mainly related to the peculiarity of the target group. Firstly, recruiting Hikikomori individuals was quite a challenging task, for this reason, we had to deal with a limited sample size to test the study hypothesis. Due to the exploratory nature of the study and the lack of scientific data related to Hikikomori fictional narrative consumption behavior, the selection of questionnaire items was not sufficiently endorsed by literature. Finally, maybe due to the difficulty in answering about psychiatric symptoms like depression and anxiety, we resulted in having participants reluctant in answering the questions which curtail the sample size even further. To overcome these limitations, a research design which includes internet survey may be the ideal solution, reaching directly to secluded Hikikomori individuals and lowering the risk of failed responses to questionnaire items.\n\n\nConclusions\n\nThis study aimed to explore the situation of empathy, relaxation, anxiety, and depression of Hikikomori individuals related to their consumption of fictional narrative productions and their emotional transportation skills. Although the relationship with anxiety and depression could not be assessed due to the limited sample size, the results obtained for empathy and relaxation are consistent with the previous research done with healthy individuals. This may suggest the possible benefits of fictional narratives on enhancing empathy and diminishing emotional tension in Hikikomori individuals. Compared to healthy people, these results could be even more meaningful for Hikikomori individuals, given that they are subject to a higher level of anxiety and impaired social behavior compared to the general population. Considering the limitations of the study and the fact that only a correlation has been proven, the results should be interpreted with caution. To test the hypothesis for emotional transportation or fictional narrative consumption behavior to be predictors of empathy, relaxation, or other psychological dimensions, future research with an interventional study design is needed for a better understanding of causality before trying to establish a new experimental approach using narrative therapy for Hikikomori individuals.\n\n\nData availability\n\nRepository: Uploaded to Harvard Dataverse\n\nPanto, Francesco, 2021, \"The Correlation between Enjoying Fictional Narratives and Empathy in Japanese Hikikomori\", https://doi.org/10.7910/DVN/8AYPKV, Harvard Dataverse, V1, UNF:6:cvasikAbeDexFrSerq36EA== [fileUNF]\n\nthis project contains the following underlying data:\n\n• Data file 1. (Test score results in empathy, relaxation depression, anxiety, narrative fiction consumption and other descriptive measures in 80 Hikikomori patients.)\n\nData are available under the terms of Harvard Dataverse “No rights reserved\"\n\n\nParticipant consent\n\nWritten informed consent for publication of the participants details was obtained from the participants/parents/guardian/relative of the participant.",
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Publisher Full Text"
}
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{
"id": "95014",
"date": "06 Oct 2021",
"name": "Ali Evren Tufan",
"expertise": [
"Reviewer Expertise statistics",
"epidemiology",
"child and adolescent psychiatry",
"developmental neuropsychiatry",
"biological psychiatry"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirstly, I would like to thank you for providing me the opportunity to review this interesting research. The authors of this multi-center, cross-sectional, clinic-based study evaluated 80 Japanese Hikikomori with self-reports evaluating empathy (Multidimensional Empathy Scale, MES); depression (CES-D), trait anxiety (STAI), self-reported relaxation (S-MARE), and narrative transportation (NTS-J). The design was exploratory and aimed to evaluate the relationships between those constructs with an eye to developing remotely applied narrative therapy for those individuals.\nThe authors report three main results;\nEmpathy levels among Hikikomori correlated with emotional transportation toward fictional narratives\n\nSelf-reported relaxation correlated with the frequency of consumption of such narratives\n\nThere were no relationships with depression and anxiety levels.\nThe study is novel and interesting and I would like to commend the authors, though with some reservations. Firstly, I believe the manuscript's prose may be improved for style, clarity, and flow. specifically;\nthe authors may add the reference for the last sentence of the first paragraph of the introduction.\n\nthe first sentence of the second paragraph of the introduction is a bit vague and this paragraph may be divided at the sentence outlining study aims.\n\nrather than \"Bandura Social Learning Theory\", \"Social Learning Theory of Bandura\" may be more appropriate.\n\nthe sentence on excluding actively secluded Hikikomori as well as the last sentence in the procedures section should be revised for grammar.\nSecondly, the methodology may be further clarified. Specifically;\nthe definition of \"high and low emotional transportation\" for comparison of depressive scores may be added.\n\nthe authors used the S-MARE in a modified manner (i.e. they asked the participants to recall their state after consumption of the fictional narrative) and as such, the scores for this instrument may be affected by recall bias.\n\nthe authors also modified the use of NTS-J and reliabilities for those modifications may be reported.\n\nThe Hikikomori status evaluation may also be improved further. The authors may add inter-rater reliabilities or whether they used consensus on status evaluations.\n\nthe authors also reported \"extensive missing values\" and that they used EM algorithms for missing data analysis but they did not report their results. Those results may be added.\n\nthe unit for age (i.e. years) may be added.\n\naccording to squared correlations, emotional transportation shared 25.0 % of the variance while fiction consumption rate and relaxation shared 9.0 %, what other factors may be responsible and be evaluated in further studies?\n\nthe authors reported using ANOVA for participants with habitual and not habitual consumption, n that case did they compare two or three groups? The first may be analyzed with a t-test.\n\nconsidering the positive correlations between depression and trait anxiety, the results of the regression analyses may be affected by multi-collinearity. This information may be added to the results.\n\nthe rationale for measuring trait anxiety (vs. state) may also be further clarified.\nLastly, both the introduction and the discussion may benefit from the inclusion of some recent and related references. Suggested references may include;\nTan et al. International experience of hikikomori (prolonged social withdrawal) and its relevance to psychiatric research.1\n\nImai et al. The characteristics of patients with severe social withdrawal 'Hikikomori' in two community psychiatry clinics in Japan.2\n\nNonaka & Sakai. Psychological Factors Associated with Social Withdrawal (Hikikomori).3\n\nHihara et al. Positive and negative valences of identities: Longitudinal associations of identity content valences with adaptive and maladaptive functioning among Japanese young adults.4\n\nHamasaki et al. Identifying Social Withdrawal (Hikikomori) Factors in Adolescents: Understanding the Hikikomori Spectrum.5\nDespite the above-mentioned limitations, the study is novel and has the potential to contribute to the literature. I commend the authors and suggest that they address those limitations which would further increase the scientific merit 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? 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": "7596",
"date": "21 Jan 2022",
"name": "Francesco Panto",
"role": "Author Response",
"response": "Thank you for your detailed and accurate comments. I appreciate greatly your contribution to our research. I tried to make the specific corrections requested. As follows the authors may add the reference for the last sentence of the first paragraph of the introduction. I added the already listed reference which points out the presence of the Hikikomori phenomenon in other countries besides Japan. the first sentence of the second paragraph of the introduction is a bit vague and this paragraph may be divided at the sentence outlining study aims. I apologize if I misunderstood, however, I divided the paragraph talking about comorbidities and the paragraph starting with the relationship with internet addiction. rather than \"Bandura Social Learning Theory\", \"Social Learning Theory of Bandura\" may be more appropriate. Thank you for your accurate comment, I fixed the text with the correct terminology. the sentence on excluding actively secluded Hikikomori as well as the last sentence in the procedures section should be revised for grammar. I apologize for the inaccurate grammar, I tried to reformulate the sentence. Secondly, the methodology may be further clarified. Specifically; the definition of \"high and low emotional transportation\" for comparison of depressive scores may be added. I added the definition of high and low emotional transportation for this study. The definition is relative and regards the score of the scale. the authors used the S-MARE in a modified manner (i.e. they asked the participants to recall their state after consumption of the fictional narrative) and as such, the scores for this instrument may be affected by recall bias. Thank you for pointing out this possibility, I added a sentence declaring the above. the authors also modified the use of NTS-J and reliabilities for those modifications may be reported. I explained the rationale for this choice as well as the pertinent literature. The Hikikomori status evaluation may also be improved further. The authors may add inter-rater reliabilities or whether they used consensus on status evaluations. I added a statement about the consensus in the Japanese psychiatric community about the scale we used as well as the literature referring to the measures. the authors also reported \"extensive missing values\" and that they used EM algorithms for missing data analysis but they did not report their results. Those results may be added. Thank you for pointing out this important detail, I added the Little’s MCAR test as well as the percentage of the missing data. However, it is necessary I can add the figure of EM algorithms pertinent to the results for each variable. the unit for age (i.e. years) may be added. I added the unit. according to squared correlations, emotional transportation shared 25.0 % of the variance while fiction consumption rate and relaxation shared 9.0 %, what other factors may be responsible and be evaluated in further studies? I tried to explain other possibilities as well as possible measures we can use in future studies. the authors reported using ANOVA for participants with habitual and not habitual consumption, n that case did they compare two or three groups? The first may be analyzed with a t-test. I apologized for the difficulty In interpreting the text. I confirm that we used ANOVA because the comparison is between 3 groups. Specifically, 1) habitual consumption 2) no habitual consumption (from time to time group ) 3) no habitual consumption (nothing at all group) considering the positive correlations between depression and trait anxiety, the results of the regression analyses may be affected by multi-collinearity. This information may be added to the results. I added the information, thank you for the indication the rationale for measuring trait anxiety (vs. state) may also be further clarified. I added the explanation for this choice in the paragraph relative to the measure used for anxiety. Lastly, both the introduction and the discussion may benefit from the inclusion of some recent and related references. Suggested references may include; Thank you for your kind remark, I appreciate your contribution searching for pertinent papers. I Added the suggestions as follows: Tan et al. International experience of hikikomori (prolonged social withdrawal) and its relevance to psychiatric research. ⇨ introduction Imai et al. The characteristics of patients with severe social withdrawal 'Hikikomori' in two community psychiatry clinics in Japan. ⇨ introduction Nonaka & Sakai. Psychological Factors Associated with Social Withdrawal (Hikikomori). ⇨ discussion Hihara et al. Positive and negative valences of identities: Longitudinal associations of identity content valences with adaptive and maladaptive functioning among Japanese young adults. ⇨ introduction Hamasaki et al. Identifying Social Withdrawal (Hikikomori) Factors in Adolescents: Understanding the Hikikomori Spectrum ⇨ discussion"
}
]
},
{
"id": "100325",
"date": "09 Dec 2021",
"name": "Gloria Hongyee Chan",
"expertise": [
"Reviewer Expertise youth in cyber space",
"hikikomori"
],
"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 giving me such a great opportunity to review this article. Based on a psychiatric perspective, this article attempts to enrich the research on Hikikomori by investigating the relationship between the engagement in fictional narratives, emotional transportation, empathy, and the psychological state (level of depression and anxiety) in Hikikomori. It seeks not only to advance the study on Hikikomori but also generate practice implications, such as the use of Narrative Therapy for supporting this group of youth.\nWhile the potential significance of the article is highly appreciated, I would like to express my concerns as follows:\n\nApart from the linkage between fictional consumption and empathy, the author could provide more illustrations for studying depression and anxiety as well.\n\nGiven that the results of the multiple regression analysis showed that the model investigating the predictability of emotional transportation and fictional consumption rate of empathy and relaxation explained 23.2% and 5% of the variance respectively, are there possibly other factors in the model, and worth noting them as a direction for future study?\n\nNarrative Therapy is suitable for deconstructing Hikikomori’s life experiences to achieve de-labeling of this group of youth and achieving empowerment of this group of youth through reconstructing their life experiences. It would be great if the author could demonstrate more the linkage of Narrative Therapy and your topic of study as practice implications.\n\nAs a minor comment, it would be great if taking another look at the citations (e.g., “According to one study conducted in South Korea, 56% of Hikikomori are at risk of internet addiction, using the internet as their only way of communicating with the world (Chan & Lo, 2014). On the other hand, it has been suggested that internet usage, being the preferred communication and social tool used by Hikikomori, could be paradoxically beneficial for a Hikikomori’s quality of life (Lee et al., 2013)” on p. 3 of the manuscript: The two references have to be swapped?)\n\nOn this account, I would suggest the author address the above concerns in order to further enhance the significance 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? 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": "7597",
"date": "21 Jan 2022",
"name": "Francesco Panto",
"role": "Author Response",
"response": "Thank you for your kind response and your time dedicated to reading and reviewing our paper. We really appreciate your important contribution. We tried to make the specific corrections requested. As follows Apart from the linkage between fictional consumption and empathy, the author could provide more illustrations for studying depression and anxiety as well. Thank you for your indication. We added an explanation about the reasons for choosing these measures in the paragraph about Fictional narratives. Given that the results of the multiple regression analysis showed that the model investigating the predictability of emotional transportation and fictional consumption rate of empathy and relaxation explained 23.2% and 5% of the variance respectively, are there possibly other factors in the model, and worth noting them as a direction for future study? Thank you for your question, I added a little paragraph in the discussion confronting the other possible measures we can use in future studies. Narrative Therapy is suitable for deconstructing Hikikomori’s life experiences to achieve de-labeling of this group of youth and achieving empowerment of this group of youth through reconstructing their life experiences. It would be great if the author could demonstrate more the linkage of Narrative Therapy and your topic of study as practice implications. Thank you for this important suggestion, I added similar programs we are taking as references and their effectiveness in the introduction, as well as similar approaches using narrative therapy with fictional narratives that we can use as a model for future studies. As a minor comment, it would be great if taking another look at the citations (e.g., “According to one study conducted in South Korea, 56% of Hikikomori are at risk of internet addiction, using the internet as their only way of communicating with the world (Chan & Lo, 2014). On the other hand, it has been suggested that internet usage, being the preferred communication and social tool used by Hikikomori, could be paradoxically beneficial for a Hikikomori’s quality of life (Lee et al., 2013)” on p. 3 of the manuscript: The two references have to be swapped?) Thank you for noticing the mistake, We apologize for missing this. I corrected as you kindly suggested."
}
]
}
] | 1
|
https://f1000research.com/articles/10-776
|
https://f1000research.com/articles/11-72/v1
|
21 Jan 22
|
{
"type": "Research Article",
"title": "Strengthening laboratory capacity for HIV vaccine clinical trials and epidemiological studies in Eastern and Southern Africa",
"authors": [
"Bashir Farah",
"Moureen Maraka",
"Mercy Mshai",
"Paramesh Chetty",
"Linda Murungi",
"Daniel Ochiel",
"Jill Gilmour",
"Moureen Maraka",
"Mercy Mshai",
"Paramesh Chetty",
"Linda Murungi",
"Daniel Ochiel",
"Jill Gilmour"
],
"abstract": "Background: Conducting successful HIV vaccine clinical trials in resource-limited settings is hampered by lack of adequate laboratory capacity at trial sites, poor infrastructure, lack of well-trained technical personnel, and inadequate laboratory quality management Systems. We describe our approach to establishing sustainable laboratory capacity for clinical trials in Africa. Methods: IAVI identified 9 CRCs where a capacity building program that supports immunology and clinical testing was established. Information from the 9 CRCs was collected retrospectively and compiled in Microsoft excel for descriptive statistics. Mapping was done in Quantum Geographic information system. Results: Newly built and refurbished laboratories have been equipped with the required testing laboratory equipment. All CRC laboratories (n=10, 100%) received Good Clinical Laboratory Practice (GCLP) accreditation between 2004 and 2016, and accreditation maintained annually. A total of 89 audits were done between 2005-2019. KAVI and KEMRI had the highest number of audits (n=11, 12.4%). IAVI successfully trained a total of 1811 individual, of which (n=1130, 62.7%) trained on GCLP, (n=330, 18.3%) Quality Management Systems, (n=311, 17,2%) laboratory techniques and (n=32,1.8%) between 2004 and 2021. All the 13 Assays were registered in either College of American pathologist (CAP) or Royal college of pathologists of Australasia (RCPA) for Proficiency testing. Conclusion: The establishment of GCLP accredited laboratories and well-trained personnel has created centers of excellence and it has enabled them to attract independent competitive research funding. The GCLP accreditation and standardized testing procedures ensured reliable and accurate data, especially important for multi-country and multi-center studies.",
"keywords": [
"GCLP",
"Clinical",
"Capacity",
"Accreditation",
"Strengthening"
],
"content": "Introduction\n\nHIV/AIDS is a major public health concern and cause of death globally. At end of 2018, nearly 37 million people were living with HIV, with the majority of infections occurring in sub-Saharan Africa.1 Despite the progress made in providing infected individuals with life-saving antiretroviral treatment and the scale up of preventive measures, 1.7 million people became newly infected with HIV in 2018.1 The development of efficacious and effective HIV vaccines is an essential strategy to end the HIV epidemic and during all stages of their development, candidate vaccines need to be assessed in areas with a high disease burden. It is therefore imperative that clinical trials of HIV vaccines be carried out in geographically relevant populations with the highest disease burden.2\n\nClinical trials of vaccine candidates in resource-limited settings can be hampered by several factors including lack of capacity of infrastructure and inadequate trained personnel, inefficient regulatory and ethical approval processes and lack of disease surveillance systems, amongst others.2 Laboratory facilities often lack quality assurance systems to ensure accurate and reliable safety and immunogenicity data that are crucial in clinical trials.3–5\n\nFor more than twenty years IAVI has been involved in HIV vaccine research and development as part of its mission to translate scientific discoveries into affordable, globally accessible public health solutions. In this regard, IAVI partnered with Clinical Research Centers (CRCs) in Eastern Africa (Kenya, Uganda and Rwanda) and Southern Africa (Zambia and South Africa). Through these partnerships IAVI has strengthened the capacity at the CRCs to conduct HIV vaccine clinical trials and epidemiological studies. One of the main components of this capacity building has been the establishment and compliance to Good Clinical Laboratory Practice (GCLP) standards,6 to ensure the results of clinical laboratory are comparable, repeatable and auditable data across the different laboratories in the network. This article describes processes implemented by IAVI to build and strengthen laboratory capacity and infrastructure in the Eastern and Southern Africa CRCs, and how GCLP compliance and accreditation was achieved and sustained in these centers.\n\nStudy locations: This was conducted in IAVI CRC laboratories.\n\n\nMethods\n\nCapacity building activities were organized in four main areas1: Infrastructure development2; Trainings3; Quality management systems; and4 Sample management. To enhance the capacity building at the CRCs, two other laboratories; Clinical Laboratory Services (CLS) in Johannesburg, South Africa and IAVI Human Immunology Laboratory (IAVI-HIL) at Imperial College in London acts as reference laboratories and provide technical support to these CRC laboratories.\n\nTo achieve infrastructure development for the selected laboratories the following were done: selection of locations for establishing fully-fledged research testing, site qualification and development of collaborating laboratories.\n\nIAVI identified 9 CRC Laboratories in Southern and Eastern Africa (Figure 1) to form the African CRC network for purposes of conducting clinical trials and epidemiological/observational studies. The criteria for selection was based on labs performing clinical safety and immunology testing, labs located within large teaching and research institutions. These CRCs required different type of laboratory support based on their various needs. Some of the laboratories existed within a research or an academic institution and were already equipped to undertake most of the required clinical safety and immunology testing. These included Kenya Aids Vaccine Initiative-Institute of Clinical Research (KAVI-ICR) laboratory at the University of Nairobi, Kenya Medical Research Institute (KEMRI) -Kilifi and Uganda Virus Research Institute (UVRI)/Medical Research Center (MRC)-Entebbe and UVRI-Iavi) located within large teaching and research campuses at KEMRI and UVRI, respectively, and the Medical Research Laboratories (MRC – Masaka) located at an MRC research site in Uganda. Although these laboratories were well established they had no previous experience in conducting clinical trials hence had no GCLP accreditation.\n\nMRC – Medical Research Council, UVRI – Uganda Viral Research Institute, LSHTM – London School of Hygiene & Tropical Medicine, KAVI – Kenya AIDS Vaccine Initiative and UKZN – University of Kwazul-Natal (QGIS software version 7.4.4).\n\nThere were also CRCs with small satellite laboratories that needed to be scaled up to a level required for conducting clinical trials. This involved upgrading infrastructure and staff training to receive full GCLP Accreditation. These CRCs included the Zambia-Emory HIV Research Project (ZEHRP-Lusaka and ZEHRP-Ndola) in Zambia, and Center for Family Health Research (CFHR) in Kigali, Rwanda.\n\nThe process involved collaboration with partners in situations where there was no existing laboratory. IAVI and the partner institution agreed on the support needed and a physical space for location for the laboratory was identified. The design of the laboratory (architectural plan) was drafted, and the actual building implemented to completion. The newly built laboratory was then equipped, staff were identified and trained in both clinical safety and immunology testing. The Aurum Institute for Health – Rustenburg (South Africa) laboratory is one example of a CRC that received this kind of IAVI support.\n\nImmunology and clinical safety testing laboratories underwent a qualification procedure prior to the initiation of any clinical testing.7 This included review of the required infrastructure (laboratory buildout, purchase and installation of equipment), assessment of compliance to GCLP and appropriate technology transfer qualifying assays. Standardized checklist was used to assess the site’s capacity to conduct the proposed clinical trial or study and the investigators were qualified by their training, education and experience, as per GCP requirement. Any gaps or other issues identified from the site qualification visits were rectified beforehand. Successful performance of qualified assays ensured that collaborating center personnel had gained adequate familiarity with equipment, SOPs and other documentation, and the correct equipment and reagents were provided.\n\nTraining of four different types were conducted to the nine CRCs within the IAVI network. The trainings were aimed at ensuring that all CRCs conduct research efficiently and to the highest ethical standards. The first type of training performed was basic GCLP. The training aimed at enhancing compliance to international standards for conducting clinical trials. The second type of training was advanced GCLP training. This training was designed to provide comprehensive guidance and practical help to ensure implementation of GCLP guidelines in all the sites conducting IAVI-sponsored clinical trials.\n\nBiosafety was the third training type performed. This training was provided by IAVI HIL who aimed at providing a structure and set of standards upon which to develop a practical and realistic health and safety program in the IAVI-supported laboratories. The assessment was conducted as a written multiple-choice test and by observation of the trainee performing the work.\n\nThe last training type was focused on advancing the technical skills of the laboratory staff from the nine CRCs within the IAVI network. This training aimed at improving the technical knowhow on the clinical and equipment procedures. These included procedures for hematology testing, ELISPOT, flowcytometry, liquid nitrogen plant and HIV testing.\n\nA four-approach implementation model was used to develop quality management system (QMS) in the CRCs and prepare them for accreditation. GCLP guidelines was used to achieve the journey of accreditation because it is the recommended guideline by World Health Organization (WHO) as the standard for clinical laboratories involved in the evaluation of diagnostics for infectious diseases.8 The implementation model was made up of four main components namely: a comprehensive audit program, External Quality Assessment program, equipment standardization and sample management. The audit program aimed at ensuring the CRCs adhere to GCLP compliance. The audit program was made of two external audits and one internal audit. The external audits were mainly accreditation assessment and a bi-annual audit by a research contract organization. The accreditation assessment audit was6 carried out by Qualogy, UK, an independent accrediting body which assesses GCLP Compliance against the Research Quality Assurance (RQA) GCLP Guideline and GCP Regulations.9 The bi-annual internal audits were performed by the Clinical Laboratory services (CLS), Johannesburg, South Africa.10 This audit was a follow-up of the findings of the accreditation assessments. The internal audit was performed by the trained site staff and was aimed at ensuring that the established QMS remains abreast compliance with GCLP standards.\n\nThe EQA implementation model involved registering all the CRCs on EQA schemes with an objective of providing accurate and reliable results. The intention of EQA schemes was to provide an independent external assessment of a laboratory's ability to provide an accurate results by comparing it to a peer group of laboratories or to a reference laboratory.11,12 EQA scheme providers were identified and CRCs enrolled on the clinical safety and immunology assays. The CLS coordinated the EQA enrollment and reports for all the CRCs in collaboration with IAVI. CLS reviewed all the CRCs’ EQA reports and worked with CRCs to ensure corrective actions were implemented where EQA results are not scored, out of range and if panels were not submitted To standardize the testing analyzers and methods across the CRCs, the hematology and clinical chemistry analyzers were purchased and distributed among the CRCs. This helped in coordinating the equipment service/maintenance management as well as purchase of their reagents and kits including performing method validation. The CLS in collaboration with IAVI gave guidance to the CRCs on how to develop the validation plans, carry out validations, review of data and development of reports using Psmile resources/tools.13\n\nTo strengthen sample management across the 9 CRCs within the IAVI network, site laboratory staff were trained on laboratory information management system (LIMS). The SQL*LIMS v5 data system (Applied Biosystems, San Jose, California) was used to manage the input, collection and analysis of data from the laboratory network. Documented procedures for sample reception and chain of custody were also developed to ensure sample integrity is maintained.\n\n\nResults\n\nIAVI has established a program that provides capacity development and support for immunology and clinical safety testing at the 10 CRC laboratories in Eastern and Southern Africa region. As a result of the infrastructure development, IAVI CRC laboratories have been accredited, developed essential documents for quality management, respective staff trained, established EQA program, methods standardized, equipment maintenance/service program developed and sample management system well established.24\n\nA total of 10 laboratories were accredited by Qualogy limited, United Kingdom between 2004 and 2016 as shown in Figure 2. The accreditation timeline was dependent on when the site was identified and their readiness for the accreditation.\n\nKEMRI – Kenya Medical Research Institute, ZEHRP – Zambia Emory HIV Research Project, HPP – HIV Pathogenesis Project.\n\nAll the laboratories went through a comprehensive audit and implemented corrective actions to address any audit findings UVRI-IAVI Entebbe, Uganda was the first site to obtain GCLP accreditation in 2004 (and the second laboratory in Africa to achieve this status), followed by KAVI-ICR, University of Nairobi Kenya in 2005. The following laboratories received their accreditation after 2005: CFHR Kigali, Rwanda (previously known as Project San Francisco, PSF); MRC Masaka, Uganda; ZEHRP Lusaka and Ndola, Zambia; KEMRI Kilifi, Kenya; AURUM Rustenburg, South Africa; HIV Pathogenesis Programme (HPP), Durban, South Africa; MRC-Entebbe, Uganda (Figure 2).\n\nDuring the period of study, a total of 82 trainings were done to 1859 laboratory staff. The highest number of trainees were in GCLP training at 61.2% (n = 1138), followed by QMS trainings at 20.3% (n = 378), technical trainings at 20.3% (n = 311) and Safety training at 1.7% (n = 32). Of the total trained for GCLP, 68% (n = 725) were trained in basic GCLP while 32% (n = 347) were trained in Advanced GCLP training (able 1). Basic GCLP training had the highest number of staff trained because all staff at each site were to be trained to understand GCLP guidelines (Table 1).\n\nBiosafety training: All of the staff who scored above 80% were deemed competent. If the score was less than 80%, trainees were retrained and were not allowed to work in the laboratory until they obtained the required results.\n\nThe number of trainees across the years were varied per training category. Basic GCLP training was consistently done at least each year followed by Advanced GCLP. The highest number of trainees were in 2008 at 102(13.6%) and 41(10.6%) in 2021 for Basic and advanced GCLP trainings respectively (Table 2). QMS based trainings were initiated in 2007 and were done every 2 years upto 2015. Thereafter the trainings were annual up to 2019 (Table 2). Safety trainings had only been done in 2018 (Table 2).\n\nTo strengthen the laboratory capacity through QMS, a total of 89 accreditation assessments audits were performed by Qualogy between 2005 and 2019. The highest number of audits (n = 10) was observed in the year 2010, 2017,2018 and 2019 as shown in Figure 3. KAVI and KEMRI had the highest number of accreditation audits (n = 11), followed by UVRI-IAVI and MRC Masaka (n = 9) and MRC Entebbe (LSHTM) had the least (n = 3) as shown in Figure 4.\n\nIn using EQA to strengthen QMS a laboratory capacity strategy, a total of three EQA scheme providers namely: CAP, RCPA and HIL were identified to provide EQA services. All the CRCs were enrolled on EQA schemes based on their testing scope covering all safety testing parameters and Elispot assay to ensure accuracy of results (Table 3). The frequency of the EQA panels is determined by the service provider and varies per assay/test.\n\nIn using standardization of testing analyzers and testing methods to implement QMS as part of laboratory capacity strengthening strategy, IAVI purchased ten chemistry analyzer, ten hematology analyzers, ten serology equipment, ten flow-cytometry equipment and ten temperature monitoring equipment which were distributed across the ten CRCs (Table 4).\n\nAdditionally, 311 number of staff were trained on the equipment, analyzers and standardized protocols to ensure accurate and reliable results are generated. HIV testing and clinical chemistry had the highest number of trainees followed by Hematology (Figure 5).\n\nA centralized SQL*LIMS v5 data system (Applied Biosystems, San Jose, California) system was purchased and implemented in all the ten CRC laboratories. All CRCs were trained on LIMS operation during the duration of the study.\n\n\nDiscussion\n\nThe capacity to conduct clinical trials/studies in Africa is limited in part, by a lack of adequate laboratory research infrastructure. Laboratory support of clinical trials/studies is integral to their quality; defining the analytical parameters for inclusion/exclusion criteria, monitoring the safety of the participants, determining the baseline data, and the safety and efficacy of the investigational products.\n\nStaff training: Well trained and organized staff are essential for the successful operation and management of a clinical laboratory for quality and reliable data. In Sub-Saharan Africa, there has been lack of advanced-level training programs for laboratory staff and this has resulted to inadequacy in the laboratory sector in the region.14\n\nBasic GCLP training had the highest number of trainings and was consistent across the years. The training is carried out for new staff or as refresher to the old staff. This implies that CRCs employ at least annually and for them to be competent in the laboratory, Basic GCLP training was to be done for them to understand the basic concepts of GCLP and the implementation process required for a clinal laboratory. As a refresher it provides staff with renewed knowledge in GCLP.\n\nBasic GCLP training was followed by Advanced GCLP in consistency and number of trainings executed. The training is need based and offered to all CRC laboratory and QA Managers every year. Need based training has been reported elsewhere to enhance Quality improvement when emphasize is put on actionable training needs.15 The aim was to discuss challenges faced when executing GCLP and get an in-depth understanding on how to interpret and implement GCLP in their respective CRCs. The basic advanced model of training used has also been reported elsewhere.\n\nQMS trainings evolved in 2007. This were in support of the already accredited CRCs and in preparation for the GCLP accreditations the new CRCs that were accredited around this time. At around this time adaption of QMS to local priorities had proven difficult in Sub Saharan Africa.16 Therefore, there was need to support the CRCs.\n\nIAVI realized that one of the novel ways to obtain the most accurate and reliable clinical trial data from multiple participating CRCs in different countries was to have the least number of variables that could affect clinical trial data and processes. In view of the latter, analyzers at IAVI participating Africa CRCs for clinical trials/studies were standardized for safety testing parameters (chemistry, haematology, serology, flow-cytometry), including standardized temperature monitored cryogenic equipment for sample storage), typical of clinical trial testing set up CRC staff were also trained on standardized methods for immunology end-point testing required for the multi-centred clinical trial/epidemiological studies. Although, this was very costly, it ensured processes were in place to obtain the most accurate and reliable data. New or upgraded equipment (chemistry and haematology) were either acquired centrally or purchased locally and placed at participating IAVI CRCs to improve technology and still maintain standardization. The centrally acquired equipment allowed IAVI to negotiate for discounts and extended warranties. The standardization also enables maintenance and training of equipment to be streamlined. As a result, SOPs and related documents were developed as recommended by WHO.17\n\nAll CRC laboratories have documented SOPs which are approved by the CRC laboratory management and are periodically reviewed by CRCs staff, in accordance with GCLP guidelines. These processes are monitored during onsite audits by IAVI. A list of current SOPs is maintained and kept up to date by the CRC’s laboratory/Quality assurance manager. To standardize the immunogenicity assays, standardized SOPs were developed and distributed to the CRCs by IAVI HIL. SOPs detailing the preparation (isolation and thawing) of human peripheral blood mononuclear cells (PBMC), plasma and serum for use in assays, counting and freezing of human PBMCs and the evaluation of interferon-γ producing cells by ELISpot assay are validated at the IAVI’s HIL prior to their distribution to CRCs laboratories. In addition, the Analytical Project manager drafts an analytical plan for each of the clinical trial/study the laboratory is undertaking. This analytical plan which details the laboratory study procedures to be followed, is agreed upon with the CRC and approved by the sponsor and the laboratory management.\n\nExternal audits by Qualogy limited were to ensure that all CRCs were accredited. CRC accreditation implies an implementation and monitoring of a comprehensive laboratory quality management systems that reduces variability of test results and laboratory errors.18 Before accreditation were awarded a baseline, audit was carried out. The CRCs were expected to close the findings prior to accreditation award. The accreditations were awarded at different time points depending on when the CRC was identified and how fast they were able to close out the findings. Accreditation has been a sign of compliance to the established quality and competence standards.18,19\n\nAs the CRCs developed and maintained GCLP compliance over the years, the frequency of the bi-annual internal audits by a research contract organization was changed from biannual to annual and the CRCs were enhanced to strengthened internal audit systems. As reported elsewhere internal audits were meant to stimulate the maintenance and improvement of quality.19\n\nEnrollment to an EQA program is mandatory in established countries.18 Prior to accreditation or implementation of study protocols, IAVI enrolls the CRC networks in identified EQA programs. enrollment in EQA programs is among the first steps of implementing a quality system.19 This ensures that analytical results are reliable globally accepted.20 Most of the HIV vaccine clinical trials are multi-site trials where vaccine immunogenicity data is generated by different CRCs. An important end-point assay for HIV and other vaccines has historically been the interferon-gamma (IFN-γ) Elispot assay.21,22 Extensive efforts have been made by IAVI and others to validate and standardize the T-cell Elispot assay. To ensure reliability of the results Elispot EQA, relevant CRCs were enrolled in the program.\n\nIAVI has established standardized protocols for validation of the assays and analyzers. All new assays are validated prior to being used and validation of new equipment is also undertaken upon installation. This has ensured that analytical results generated across the CRCs are dependable.23 This is a documented program of work intended to evaluate or demonstrate the performance of a process. Validation protocols are developed in conjunction with the CRC laboratories. Data is generated, and the results are compared against pre-defined acceptance criteria. In addition, all CRCs assess and document lot-to-lot verification of new reagent performance. This is because performance of new reagent lot can be affected by several factors including instability of reagent during transportation or storage, and defects in manufacturing. A standardized protocol has been developed to assess the lot-to-lot verification.\n\nAvailability of properly functioning laboratory equipment with appropriate maintenance is critical to the conduct of clinical research and the production of reliable and accurate results, however in developing countries it can be an enormous challenge.24 Laboratory equipment requires regular maintenance as recommended by the manufacturers. The maintenance of laboratory equipment requires a wide range of technical abilities and skills and laboratories must have a preventative maintenance contract with engineers from the manufacturers, their agents, or appropriately trained biomedical engineers.\n\nOne of IAVI’s focus has, been to strengthen and equip laboratories in its clinical research centers. IAVI has provided financial assistance to procure state of the art laboratory equipment for the safety and immunology laboratories. Among this equipment were hematology, serology & chemistry analyzers, Elispot readers, flow cytometry, deconvoluted microscopes, liquid nitrogen plants, and cryogenic equipment as shown in Table 3. IAVI has also procured generators and uninterrupted power supply (UPS) to provide continuous backup power to essential equipment in the laboratory and pharmacy.\n\nA comprehensive equipment maintenance and service program is managed by IAVI. Independent biomedical engineering companies who have the skills, tools and the necessary experience to maintain laboratory equipment are contracted to perform such work. The service and maintenance program are undertaken twice annually at all participating collaborating CRC. The external vendors provide a written report for each CRC laboratory of the work carried out, problems encountered and the proposed resolution. They also maintain a list of small spare parts required by the CRCs and the small spare parts are replaced during the service visit. In the event a major spare part is required to be replaced, an order is generated and submitted to the manufacturer of the equipment. To ensure proper functioning of the laboratory equipment laboratory staff at each CRC was trained to perform regular preventive maintenance as recommended by the manufacturer. In addition, each CRC laboratory was provided with toolkits to make minor repairs like electric fuse replacement.\n\nAll CRC laboratories have SOPs and procedures for sample receipt, preparation and processing. Documenting chain of custody and sample integrity is a standard practice across centers. Samples collected in the clinic are given unique identifiers using automated sample labeling. A study/visit specific laboratory requisition form is sent with the samples to the laboratory. All samples received are logged into the laboratory information management system (LIMS). The SQL*LIMS v5 data system (Applied Biosystems, San Jose, California) is used to manage the input, collection and analysis of data from the laboratory network. The LIMS web-based interface allows for remote data entry, centralized technical management and near real-time access to data and sample inventory. The system is highly customizable and offers electronic signatures as well as an automatic audit trail and user security checks and data integrity. The HIL laboratory oversees quality assessment of processing, storage and shipment of PBMC samples across the IAVI CRC network. All sites have staff who have been trained on LIMS and the system has been operational at these centers for several years in support of IAVI funded studies/trials. This efficient, centralized sample management system is utilized for all the IAVI supported CRCs with support from IAVI HIL. To date, the HIL has managed the custody of over seven hundred thousand samples from a global network of CRCs and collaborative partners. On average 8,000 to 12,000 (15-20 shipments per year) samples per year were shipped to HIL from IAVI CRCs. Only one failed shipment (Dec 2017) has occurred within the past 15 years. The sample repository, which is based at the HIL has a storage capacity of over 900,000 specimens in both liquid nitrogen vapor tanks and ultra-low temperature (−80°C) freezers, managed by a customized GCLP compliant LIMS.\n\nHigh quality standards in international shipping practices have led to a standardised procedure of 7-day calibrations of dry shippers for the shipment of PBMCs. PBMCs are the main samples obtained for cell based immunological assays, which are typically integral to measuring the immunogenicity of vaccine clinical trials. The cold chain from PBMC preparation, storage, shipping, through to sample use is controlled and closely monitored, with alarm systems and back up corrective procedures in place at all laboratories. The relevant staff at each site is trained to meet the minimum requirements for dangerous goods according to 49 CFR 172.700 and IATA 1.5 and to ensure that the shipment is compliant with these regulations. This is achieved by completing the training in the SAF-T-PAK that is shipped to CRCs laboratories every 2 years.\n\nThe IAVI Africa laboratory program with the support of the IAVI HIL has enabled real-time safety testing and state-of-the-art immunology assays at all their affiliated facilities. Infrastructure development, training, site support visits, and ongoing quality assurance programs were essential parts of setting up a network of African laboratories conducting clinical trials. The Quality Assurance (QA) programs have shown that the labs at the research centers in Africa can perform clinical assays consistently in line with counterparts in industrialized countries\n\nWith IAVI’s support, laboratories at CRCs have received GCLP accreditation and standardized testing procedures to ensure reliable and accurate data, especially for multi-center studies. The establishment of GCLP accredited laboratories in Eastern and Southern Africa with well-trained personnel has created centers of excellence and allowed these CRCs to attract independent research funding.\n\nStandardization of laboratory equipment at IAVI sponsored sites has allowed efficient training, maintenance, and easier purchase of spare parts. The centralized vendor is based in Kenya oversees this process for all CRCs which are part of the IAVI network. Standardized temperature monitoring systems are included, and these can be evaluated across CRCs which ensures that equipment downtime and service interruptions are minimized.\n\nThe IAVI HIL coordinates and supports the flow of samples across the network of clinical trial laboratories ensuring full chain of custody of all specimens collected. The HIL Unit, which includes IAVI QA Africa and HIL-London have consistently maintained and driven the expansion of capacity of the CRCs within the IAVI network to support high quality sample management infrastructure.\n\n\nConclusion\n\nIAVI’s continued capacity building across the CRCs in Africa has led to the following: 1) Transfer of clinical research skills to African researchers to support clinical trial programs and a broad range of epidemiological studies at the research sites2; Implementation of quality systems and standardized testing procedures leading to generation of reliable and attributable data, especially for multi-center studies across various countries3; Participation in EQA programs, which enables comparison of performance between laboratories globally and provides an early warning for systematic errors; and4 Ability to conduct and participate in clinical trials and epidemiological studies.\n\n\nAuthor contributions\n\nBF contributed towards conceptualization, data collection, drafting and final revisions of the manuscript. MMaraka contributed to the technical content, Analyzed data,created the figures and tables and revision of the manuscript. MMshai contributed to the technical content of the information and conducted the technical and GCLP trainings, PC contributed towards revising the manuscript and oversaw the capacity building of the laboratories at the CRCs. LM contributed towards the intellectual content and the final revisions of the manuscript. DO is the Director of IAVI Africa laboratory program and oversaw the capacity building projects and conceptualization of the manuscript. JG is the Executive Director for HIL at IAVI and contributed towards conceptualization of the laboratory capacity building program and contributed to GCLP accreditation program in all the CRCs. All authors read and approved the final manuscript.\n\n\nData availability\n\nFigshare: GCLP Audits and Training Raw Data, https://doi.org/10.6084/m9.figshare.16817482.v1.25\n\nThis project contains the following underlying data:\n\n- GCLP Audits Raw Data.xlsx\n\n- Training data Raw.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4).",
"appendix": "Acknowledgments\n\nSpecial thanks to laboratory staff and management of the ten clinical research centers in Eastern and Southern Africa. This manuscript was submitted for publication with the permission of all the authors.\n\n\nReferences\n\nUNAIDS: UNAIDS DATA 2018.2018 [cited 2019 May 10]. Reference Source\n\nKochhar S, Rath B, Seeber LD, et al.: Introducing new vaccines in developing countries. Expert Rev. Vaccines. 2013; 12(12): 1465–1478. PubMed Abstract | Publisher Full Text\n\nFitzgibbon JE, Wallis CL: Laboratory challenges conducting international clinical research in resource-limited settings. J. Acquir. Immune Defic. Syndr. 2014 Jan 1 [cited 2019 May 10]; 65(0 1): S36–S39. Publisher Full Text Reference Source\n\nCrucitti T, Fransen K, Maharaj R, et al.: Obtaining Valid Laboratory Data in Clinical Trials Conducted in Resource Diverse Settings: Lessons Learned from a Microbicide Phase III Clinical Trial. PLoS One. 2010; 5(10): 1–8. Publisher Full Text\n\nPetti CA, Polage CR, Quinn TC, et al.: Laboratory Medicine in Africa: A Barrier to Effective Health Care. Clin. Infect. Dis. 2006; 42(3): 377–382. PubMed Abstract | Publisher Full Text\n\nStiles T, Grant V: Good Clinical Laboratory Practice clinical trials. Research Quality Association (RQA). 2012; 1–28. Reference Source\n\nSarzotti-kelsoe M, Cox J, Cleland N, et al.: Evaluation and Recommendations on Good Clinical Laboratory Practice Guidelines for Phase I – III Clinical Trials. PLoS Med. 2009; 6(5): 1–5. Publisher Full Text\n\nWHO: WHO Handbook: Quality practices in basic biomedical research. WHO; 2013. Reference Source\n\nQualogy - Regulatory Archiving Services and Consultancy.[cited 2021 Jun 4]. Reference Source\n\nUniversity of Witwatersrand: 404 - Wits University.2019 [cited 2019 May 10]. Reference Source\n\nClinical and Laboratory standard institute: Using Proficiency Testing and Alternative Assessment to Improve Medical Laboratory Quality. 3rd Editio.2016 [cited 2019 May 10]. Reference SourceReference Source\n\nMiller WG, Jones GRD, Horowitz GL, et al.: Proficiency Testing/External Quality Assessment: Current Challenges and Future Directions CONTENT. Clin. Chem. 2011; 57(12): 1670–1680. PubMed Abstract | Publisher Full Text\n\nResources — pSMILE Portal: [cited 2021 Jun 4]. Reference Source\n\nNsubuga P, Johnson K, Tetteh C, et al.: Field epidemiology and laboratory training programs in sub-saharan Africa from 2004 to 2010: Need, the process, and prospects. Pan Afr. Med. J. 2011; 10(November): 0–12. Publisher Full Text\n\nKim Ong S, Donovan GT, Ndefru N, et al.: Strengthening the clinical laboratory workforce in Cambodia: a case study of a mixed-method in-service training program to improve laboratory quality management system oversight. Hum. Resour. Heal. 2020; 18: 84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarbé B, Yansouni CP, Affolabi D, et al.: Implementation of quality management for clinical bacteriology in low-resource settings. Clin. Microbiol. Infect. 2017; 23(7): 426–433. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Good Clinical Laboratory Guideline.2009; 6–22. Reference Source\n\nPeter TF, Rotz PD, Blair DH, et al.: Impact of laboratory accreditation on patient care and the health system. American Journal of Clinical Pathology. American Society of Clinical Pathologists. 2010; 134: 550–555. PubMed Abstract | Publisher Full Text\n\nZima T: Accreditation of Medical Laboratories – System, Process, Benefits for Labs. J. Med. Biochem. 2017 Sep 1 [cited 2021 Jul 12]; 36(3): 231–237. Publisher Full Text | . Free Full Text\n\nSciacovelli L, Secchiero S, Padoan A, et al.: External quality assessment programs in the context of ISO 15189 accreditation. Clin. Chem. Lab. Med. 2018 Oct 1 [cited 2021 Jul 12]; 56(10): 1644–1654. PubMed Abstract | Publisher Full Text\n\nVuola JM, Keating S, Webster DP, et al.: Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers. J. Immunol. 2005 Jan 1 [cited 2019 May 10]; 174(1): 449–455. PubMed Abstract | Publisher Full Text\n\nRussell ND, Hudgens MG, Ha R, et al.: Moving to Human Immunodeficiency Virus Type 1 Vaccine Efficacy Trials: Defining T Cell Responses As Potential Correlates of Immunity. J. Infect. Dis. 2003; 187(2): 226–242. PubMed Abstract | Publisher Full Text\n\nPum J: A practical guide to validation and verification of analytical methods in the clinical laboratory. Adv. Clin. Chem. 2019; 90: 215–281. PubMed Abstract | Publisher Full Text\n\nFonjungo PN, Kebede Y, Messele T, et al.: Laboratory equipment maintenance: a critical bottleneck for strengthening health systems in sub-Saharan Africa?. J. Public Health Policy. 2012 Feb 10 [cited 2019 May 10]; 33(1): 34–45. PubMed Abstract | Publisher Full Text\n\nFarah B, Maraka M, Mshai M, et al.: GCLP Audits and Training Raw Data, Figshare.Publisher Full Text"
}
|
[
{
"id": "123209",
"date": "17 Feb 2022",
"name": "Moses Muia Masika",
"expertise": [
"Reviewer Expertise Infectious Diseases",
"global Health",
"One 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\nSpecific Comments:\nABSTRACT:\n\nBackground:\nThe wording could be tweaked to indicate specific limitations. Capacity and infrastructure may mean different things to different persons.\n\nMethods:\nShould define the acronym 'CRC' on first use.\n\nCurrent wording indicates that establishing a capacity building program was done in the study. It should be tweaked to show that the program was established before and the study is being conducted retrospectively.\n\nResults:\nDiscordance between the number of CRCs included (9 or 10?).\n\nIs the number of audits (n=11, 12.4%) cited for KAVI & KEMRI a summation or for each lab?\n\nThe statement reporting number of individuals trained appears incomplete?\n\nThe last sentence in this section refers to 'the' 13 assays but this number or assays has not been mentioned before. It needs to be rephrased for clarity.\n\nConclusion:\nRefers to research funding which sounds disconnected from the rest of the abstract as funding hasn't been highlighted in the methods and results section of the abstract.\n\nTypos:\nSystems in abstract background.\n\nIndividual - Abstract, results.\n\nINTRODUCTION:\nParagraph 1: consider update the HIV numbers using the latest UNAIDS data.\n\nParagraph 2: consider replacing 'ethical approval' with 'ethical review'.\n\nThe last sentence (on study locations) appears misplaced/hanging.\n\nThe authors should cite current UNAIDS Data in the introduction.\n\nMETHODS:\nThe methods section describes the process of capacity building. It also needs to describe the source(s) of the data/information presented.\n\nMethods section does not describe fully the sources of information or data presented.\n\nTypos:\n\nParagraph 1: acts (as reference labs).\n\nParagraph 3: I would rephrase this sentence: \"The criteria for selection was based on labs performing clinical safety and immunology testing, labs located within large teaching and research institutions\".\n\nTo read the criteria for selection was capacity to perform clinical.... and location within large....\n\nType (of laboratory).\n\nThe name' Kenya Aids Vaccine Initiative-Institute of Clinical Research (KAVI-ICR)' should read as KAVI Institute of Clinical Research (with KAVI being a noun not an acronym). This is also in Figure 1.\n\nPage 4 paragraph 2: Define GCP on first use.\n\nRESULTS:\nPage 9 paragraph 1: Rephrase the part on temperature monitoring system to indicate that it is for lab equipment/space (not, for instance, to be mistaken for body temperature monitoring).\n\nTable 4:\nCombining different data in the same row is a bit confusing to the reader. e.g. for row 1, one might think that the LSR Fortessa X20 is a chemistry analyzer.\n\nIt would be helpful to include the type of equipment, not just the brands e.g. BD FACS Melody Cell Sorter to give an indication of what the equipment is used for.\n\nRow 4 should read Deconvolution Microscope?\n\nThe asterisk could be replaced with \"All (CRC)s\" since the words can fit within the cell.\n\nFigure 5:\n\nLooks misplaced, could be moved to the relevant section.\n\nNot clear what the numbers are referring to. The caption and title should be reviewed to give additional details.\n\nTypos:\nPage 7 paragraph 1: done at least once a year.\n\nClarify if it's 9 or 10 CRCs/labs.\n\nThe caption for Figure 4 appears to have been merged with a paragraph of unrelated text.\n\nDISCUSSION:\nParagraph 2: The phrase 'there has been lack of advanced-level training programs for laboratory staff' sounds very general and broad. Could help by specifying the training/courses. Advanced level could also mean master/PhD or other post-graduate training which is actually available and ongoing in the continent.\n\nParagraph 3: The inference that since Basic GCLP was done every year, CRCs were hiring every year is strenuous. This should be revised. The higher demand for Basic GCLP could be due to several reasons - new staff, staff undergoing refresher training or the 'supply,' side of the training (that the course was offered every year and so people attend).\n\nQMS evolved in 2007... Is this to mean changed/modified? The subsequent text in the doesn't seem to clarify this issue.\n\nSub-headings within the discussion section should be done away with.\n\nAlthough this paper doesn't quite fit the typical IMRAD format, some of the information in the discussion (e.g. quality management processes) could fit better in the results as a qualitative analysis of sorts..\n\nThe discussion could touch on similar activities elsewhere, if any, and highlight some of the benefits of the program e.g. by citing published trials that have been conducted at the CRCs in order to demonstrate the level of capacity attained.\n\nTypos:\nTo reduce word count and improve readability, some superfluous words can be eliminated, e.g. lack of adequate lab capacity = inadequate lab capacity.\n\nParagraph 2: Delete 'Staff Training:'.\n\nSub-Saharan should be sub-Saharan.\n\nCONCLUSION:\nNo data has been presented to support the conclusion that the capacity building program enabled labs to receive funding from other sources.\n\nData sharing:\nExcel file with GCLP audit Raw Data should be anonymized so that the audit findings do not show the name of the auditor or the specific lab (a CRC number should be assigned).\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? Partly",
"responses": []
},
{
"id": "160602",
"date": "09 Feb 2023",
"name": "Syed Hani Abidi",
"expertise": [
"Reviewer Expertise Viral (HIV) 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\nFarah et al. described a step-wise approach for Strengthening laboratory capacity for HIV vaccine clinical trials and epidemiological studies in Eastern and Southern Africa. The article is clearly written and describes an important approach to HIV laboratory capacity building and quality enhancement. I have a few minor suggestions that the authors should consider to further strengthen the article:\nLaboratory selection, development/expansion:\n‘The criteria for selection was based on labs performing clinical safety and immunology testing, labs located within large teaching and research institutions.’: The authors should give a criteria table with a detailed list of essential and non-essential items (criteria) that were used to identify a site. How were the criteria between different sites standardized?\n\n‘There were also CRCs with small satellite laboratories that needed to be scaled up’: Again, what activities were included in the laboratory scale-up? What is done against the set standards or framework?\n\nSelection of locations for establishing fully-fledged research testing laboratories:\n‘The design of the laboratory (architectural plan) was drafted, and the actual building implemented to completion. The newly built laboratory was then equipped, staff were identified and trained in both clinical safety and immunology testing.’: Since this article talks about capacity-building activities, I believe it is important to mention the financial sources or support received to design new laboratories.\nOther:\nMention the full form of abbreviations at first usage.\n\nInterferon-gamma (IFN-γ) Elispot assay is mentioned as the key assay. Any assay for antibody responses was included? If yes, mention.\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? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-72
|
https://f1000research.com/articles/11-71/v1
|
21 Jan 22
|
{
"type": "Research Article",
"title": "Mitigating unbalanced and overlapped classes in credit card fraud data with enhanced stacking classifiers system",
"authors": [
"Nur Amirah Ishak",
"Keng-Hoong Ng",
"Gee-Kok Tong",
"Suraya Nurain Kalid",
"Kok-Chin Khor",
"Keng-Hoong Ng",
"Gee-Kok Tong",
"Suraya Nurain Kalid",
"Kok-Chin Khor"
],
"abstract": "Background: Credit cards remain the preferred payment method by many people nowadays. If not handled carefully, people may face severe consequences such as credit card frauds. Credit card frauds involve the illegal use of credit cards without the owner’s knowledge. Credit card fraud was estimated to exceed a $35.5 billion loss globally in 2020, and results in direct or indirect financial loss to the owners. Hence, a detection system capable of analysing and identifying fraudulent behaviour in credit card activities is highly desirable. Credit card data are not easy to handle due to their inherited problems: (i) unbalanced class distributions and (ii) overlapping classes. General learning algorithms may not be able to address and handle the problems well. Methods: This study addresses these problems using an Enhanced Stacking Classifiers System (ESCS) that comprises two sequential levels. The first level is an excellent classifier for detecting normal credit card transactions (the majority class), while the second level contains stacking classifiers that distinguish credit card frauds (the minority class). The ESCS can improve the fraud detection via the second level, which contains sensitive classifiers to identify the misclassified fraud transactions as normal transactions from the first classifier. The meta-classifier then combines the decisions of the base classifiers from the levels to produce the final detections. Results: We evaluated the ESCS using the benchmark credit card fraud dataset (CCFD) that exhibits the two problems. The highest true positive rate (TPR) for detecting credit card frauds was 0.8841, which outperformed the single classifiers, bagging, boosting, and other researchers’ works. Conclusions: This study proves that the ESCS, with an additional level added to the stacking classifiers, can improve fraud detection on credit card data.",
"keywords": [
"Enhanced Stacking Classifiers System",
"Unbalanced Class Distribution",
"Overlapping Classes",
"Credit Card Frauds"
],
"content": "Introduction\n\nCredit cards were first introduced in the USA in the early 20th century, and in Malaysia in the mid-1970s.1 Its usage has increased, and it is now widely used in financial transactions around the world. This growth, however, has led to an increase in the number of cases of fraudulent transactions using these cards.\n\nCredit card fraud can be defined as the unlawful use of any system or criminal activity involving a physical card or card information, without the cardholder’s knowledge.2 Based on the study by Ref. 3, credit card fraud detection relies on the automatic analysis of recorded transactions to detect fraudulent behaviour. When a credit card is used, transaction data consisting of several attributes (e.g. credit card identifier, transaction date, recipient, transaction amount) are stored in a service provider’s database.\n\nAccording to the Nilson report,4 between 2015 and 2020, card fraud worldwide was expected to lead to a total loss of $183.29 billion. In 2020, global card fraud was estimated to exceed $35.54 billion. Credit card frauds have thus become a major issue in society.5\n\nNumerous fraud detection studies have consistently proposed seamless approaches to overcome this issue. However, credit card data sets are not easy to handle as they usually present two challenging characteristics, i.e., (i) unbalanced class distributions and (ii) overlapping classes. Such characteristics are difficult for general classification algorithms to learn and detect credit card frauds.\n\nAccording to Refs. 6–8, an unbalanced class distribution is said to happen when some classes in a data set have a much greater number of samples than the other classes (Figure 1). Classes with more samples are called the majority class, while on the other hand, classes with a few samples are called the minority class. In a credit card data set, legitimate transactions are the majority class, whereas frauds are the minority class. Fraudulent transactions happen infrequently compared to legitimate transactions, and the percentage of fraudulent transactions is typically low.\n\nHaving a few instances of one class means that the general learning algorithms are often unable to generalise their behaviour. Consequently, the algorithms tend to misrepresent a fraudulent transaction as a legitimate transaction.9\n\nFurthermore, most general learning algorithms maximise their effectiveness based on classification accuracy, which is not a good metric for evaluating their performance in classifying unbalanced data sets. Learning algorithms usually assume an even distribution of samples for both classes.10,11 It has caused the general learning algorithms to be overwhelmed by the majority class, hence, perform poorly on the minority class.\n\nOverlapping classes in data sets occur when samples in a minority class are overlapped with samples in a majority class (Figure 2), as the samples share common regions in feature space. When overlapping occurs, it causes difficulties for the general learning algorithms to identify the small class samples.12–14 Overlapping classes also occur when minority class samples are located near the decision boundary of a majority class. Thus, the decision boundary of a minority class and a majority class may overlap.15–17 A decision boundary is a borderline that separates the regions of different classes in a data set. When the overlapping scenario is combined with the unbalanced class distribution problem, it gives rise to even more difficulties for general learning algorithms in classifying the samples.\n\nHusejinovic18 performed a study on credit card fraud detection using the single classifiers Naïve Bayes and C4.5, and the ensemble classifier Bagging. Bagging consists of a group of “weak learners” to form “strong learners” and uses majority voting to identify the predicted class by selecting the class with the highest vote assigned by the base learners.19–21 The researcher conducted experiments on the credit card fraud dataset (CCFD) and investigated the performance of these classifiers through recall, precision, and precision-recall curve (PRC) area rates; PRC was chosen as the main indicator for the study. PRC measures the overall ability to distinguish between binary classes to predict whether a transaction is normal or fraudulent. A higher PRC indicates that the model was performing better. We observed that the fraud detection rates were 0.8 for single classifiers and bagging, and still have room for improvements.\n\nDivakar and Chitharanjan22 also experimented with the CCFD to study the role of boosting classifiers. Boosting is a classification method where each classifier tries to correct the previous classifiers by adding more weights to the previously misclassified sample, and these weighted samples are then given more attention when classified by the next classifiers.23 Three classifiers, namely, AdaBoost, Gradient Boost, and XGBoost, were selected. The researchers managed to achieve a fraud detection rate for AdaBoost (0.69), Gradient boosting (0.72), and XGBoost (0.83), with model accuracies of 99.9%, 99.9%, and 100%, respectively. We can see that the classifiers performed averagely based on the fraud detection rates. The researchers also used the model accuracy as the metric for their performance evaluation. Accuracy is not a suitable performance metric when using unbalanced datasets, as classifiers maximise accuracy and are more biased towards the majority class. Kalid et al.24 used a multiple classifier System (MCS), which utilised a cascading decision combination strategy to detect frauds. The MCS was tested on the credit card fraud dataset. Using this technique, the output of the first classifier was an input of the subsequent classifier, where the samples were classified several times. The classifiers used were C4.5 (which is good at classifying the majority class) for the first level, and Naive Bayes (for classifying the minority class) for the second level. The fraud detection rate achieved by the researchers was 0.872. This result is good, but there is still room for improvement. Sailusha et al.25 also classified transactions in the CCFD using Random Forest and AdaBoost. The fraud detection rate achieved by Random Forest was 0.77 and 0.64 for AdaBoost. The results were average.\n\nAs single classifier and ensemble classifier cannot perform well in detecting credit card frauds, we proposed designing the enhanced stacking classifiers system (ESCS) to solve the two main characteristics presented by the credit card data mentioned above. ESCS is a multiple classifiers system that consists of two sequential levels. We integrated a single classifier on the first level, with stacking classifiers on the second level. Wolper first proposed stacking,26 a learning technique that combines multiple classifications through a meta-classifier.27 The meta-classifier then combines all base classifiers’ decisions to produce a final detection. We evaluated the proposed ESCS using the credit card fraud dataset (CCFD), which exhibits unbalanced class distributions and overlapping classes, as mentioned earlier. We describe the detail of ESCS in the following section.\n\nThis work has been granted ethical approval (Approval Number: EA0532021) by the Research Ethics Committee (REC) of Multimedia University.\n\n\nMethods\n\nIn this study, we used a publicly available CCFD released by Ref. 9, which was collected and analysed during a research collaboration between Worldline and the Machine Learning Group of Université Libre de Bruxelles (ULB) on big data mining and fraud detection. The dataset comprises 31 numerical variables, as shown in Table 1. Variables V1 to V28 are the transformation resulting from a principal components analysis (PCA). The original variables and more background information cannot be provided due to confidentiality concerns. The only variables which have not been transformed using PCA are ‘Time’ and ‘Amount’. ‘Time’ refers to the time elapsed between each transaction and the first transaction in the dataset in seconds. ‘Amount’ is the transaction amount. ‘Class’ is the target variable, and it indicates whether the case is a fraud, marked as ‘1’, or normal, marked as ‘0’.\n\nThe CCFD contains credit card transactions made by European credit cardholders over two days in September 2013. It is highly unbalanced: out of 284,807 transactions, 492 were frauds, and the remaining 284,315 were labelled as legitimate transactions. Figures 3 and 4 depict the unbalanced class distributions and overlapped classes of the dataset, which are the main issues to be tackled in this study.\n\nClass ‘0’ in blue represents the majority class (normal transactions), and Class ‘1’ in orange is the minority class (fraudulent transactions). As shown in Figures 3 and 4, the attributes involved overlapped with each other, and the samples in the majority class outnumbered the minority class. These characteristics also cause difficulties for general learning algorithms to detect credit card frauds effectively.\n\nAn enhanced stacking classifiers system (ESCS) is proposed to address the class distributions and overlapping issues. It was strategically designed by separating the classes and tackling the data individually at different levels to improve fraud detection rates. ESCS incorporates two sequential levels of multiple-classifier system. The first level contains a classifier that is excellent at detecting normal credit card transactions (the majority class), while the second level consists of single-level stacking classifiers that are good at distinguishing credit card fraud (the minority class). The fraudulent data that were misclassified as normal data, sorted by the classifier on the first level, were filtered out and passed to the second level for re-classification. The re-classification in the second level was performed using two base classifiers stacked with a meta-classifier. These base classifiers are more sensitive classifiers for identifying the misclassified frauds that passed the first level. The meta-classifier was used to combine the base classifier’s decisions to produce the final detection. The framework of ESCS is shown in Figure 5.\n\nPseudocode 1. Algorithm for ESCS fraud detection\n\nIn this study, five-fold cross-validation was conducted on the CCFD, ccfd. The dataset was divided into five partitions with equal distribution of normal and fraud data (Line 5, Pseudocode 1). A single partition was reserved at each validation step as the test set, Test_ccfd (Line 8, Pseudocode 1), while the remaining four partitions were used as the training data, Training_ccfd (Line 9, Pseudocode 1). This process was then repeated five times until every partition was used for training and testing. On the first level, classifier C1 was trained with Training_ccfd (Line 10, Pseudocode 1) and classified Test_ccfd with it (Line 11, Pseudocode 1). Classifier C1 is a strong classifier of the majority class (normal data).\n\nDuring classification, if the samples were classified as ‘1’, then they were appended to ccfd(1), which stores all the fraud data (Line 14, Pseudocode 1). If the samples were classified as ‘0’, they were appended to ccfd(0) (Line 16, Pseudo. 1). The ccfd(0) dataset stores all data predicted as normal and is passed to the second level to re-classify the data.\n\nOn the second level, we conducted the five-fold cross-validation on ccfd(0) again, divided into five partitions with equal distribution of normal and fraud data, and labelled them P1 to P5 (Line 21, Pseudocode 1). At each validation step, a single partition was reserved as the test set, Test_ccfd(0) (Line 23, Pseudocode 1), while the remaining four partitions were employed as the training data, Training_ccfd(0) (Line 24, Pseudocode 1). A single level stacking classifier, which consisted of classifiers C2, C3 and the meta-classifier, was trained with Training_ccfd(0) (Line 25, Pseudocode 1) and classified Test_ccfd(0) (Line 26, Pseudo. 1) with it. Classifiers C2 and C3 are strong at classifying the minority class.\n\nDuring re-classification, if the samples were classified as ‘1’, then the samples were appended to data set ccfd(1) (Line 29, Pseudocode 1), and the same samples were deleted in the ccfd(0) to avoid any redundancy in both data (Line 30, Pseudocode 1). If the samples were classified as ‘0’, then they were still stored in ccfd(0).\n\nccfd(1) and ccfd(0) were then combined and saved as ccfdFinal (Line 34, Pseudocode 1). From ccfdFinal, only the ‘Class’ column (Line 35, Pseudo. 1) and the ‘Predicted’ column (Line 36, Pseudocode 1) were retrieved to form the confusion matrix (Line 37, Pseudo. 1) as in Table 2. Lastly, the final true positive rate (TPR) score for the minority and majority classes was calculated (Lines 38-39, Pseudocode 1) as in Equation (1) and Equation (2).\n\n\nResults and discussion\n\nWe conducted three experiments on the CCFD; single classifiers, bagging and boosting classifiers, and the proposed ESCS model. Their TPR, area under the receiver operating characteristic (ROC AUC) and accuracy, were calculated and are presented in the following tables.\n\nFor the single classifier experiment, seven classifiers were used, namely, naïve Bayes (NB), ID3, logistic regression (LR), random forest (RF), multi-layer perceptron (MLP), K-nearest neighbour (KNN) and CART. Overall, we observed good accuracy, where the algorithms achieved scores above 0.99, except KNN (0.4226), CART (0.7995) and RF (0.8030) (Table 3).\n\nGenerally, the algorithms could not perform well on the minority class. TPR (1) = true positive rate for minority class; TPR (0) = true positive rate for majority class; ROC AUC = area under the receiver operating characteristic.\n\nThe TPR results were good for the majority class (class 0). This experiment yielded scores over 0.99 for most classifiers, except KNN (0.4227), CART (0.7996) and RF (0.8030). It was found that the best achievable TPR for the minority class (class 1) was only 0.7947 (RF), followed by 0.7927 (MLP), with a slight difference of 0.002. Then, it was followed by ID3 (0.7520), CART (0.7398), NB (0.6585), LR (0.6402) and KNN (0.3638).\n\nWe then tried to improve the detection rate using bagging and boosting (ensemble classifiers) since the single classifiers did not perform well in detecting frauds. This experiment involved one bagging classifier and five boosting classifiers: AdaBoost, gradient boosting, extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM) and CatBoost.\n\nAs shown in Table 4, we can achieve a good overall accuracy rate and TPR for the majority class. The highest accuracy recorded was CatBoost by 0.9993, followed by AdaBoost (0.9979), LightGBM (0.9944), XGBoost (0.9939), bagging (0.8028) and Gradient boosting (0.8004). Similarly, for TPR for the majority class (class 0), CatBoost achieved the highest accuracy by 0.9996, followed by AdaBoost (0.9984), LightGBM (0.9953), XGBoost (0.9942),bagging (0.8028) and gradient boosting (0.8009). However, the overall TPR for the minority class (class 1) was not promising, being an average value. The highest fraud detection rate was 0.7846 by XGBoost and CatBoost. The second best was performed by the bagging classifier, with a value of 0.7744. Finally, it was followed by AdaBoost (0.6931), Gradient Boosting (0.5264) and LightGBM (0.4593).\n\nFraud detection rates achieved by the classifiers were still not performing at their best. TPR (1) = true positive rate for minority class; TPR (0) = true positive rate for majority class; ROC AUC = area under the receiver operating characteristic.\n\nWe then designed an ESCS, comprising two sequential levels, to alleviate the two inherited problems of the credit card fraud data (Figure 6). On the first level, we used ID3, which is a strong classifier of the majority class (refer to Table 3). Then, the fraud data that misclassified as normal data were filtered and passed through the second level. On the second level, we used MLP and RF (refer to Table 3), which efficiently classify the minority class, and stacked them with a meta-classifier. These classifiers are more sensitive and identify the misclassified fraud detection from the ID3 at the first level. The meta-classifier was used to combine the decisions of the base classifiers to produce the final detection. We evaluated five different classifiers for the meta-classifier, namely, ID3, RF, LR, NB and MLP. All the classifiers were chosen based on their performance on the CCFD. The ESCS can improve the fraud detection rate through the second level as it contains stacking classifiers that are effective at distinguishing credit card frauds. The ESCS framework is shown in Figure 6 below, and its performance is shown in Table 5.\n\nThere were improvements in the fraud detection rate compared to single classifiers, bagging and boosting. TPR (1) = true positive rate for minority class; TPR (0) = true positive rate for majority class; ROC AUC = area under the receiver operating characteristic.\n\nWe observed that NB was the best meta-classifier combining all the base classifiers’ decisions to produce the final decision. It attained a 0.8841 fraud detection rate overall. It showed a good non-fraud detection rate of 0.9839, a ROC AUC score of 0.9340 and an accuracy of 0.9837. We could also achieve comparable accuracy rates and non-fraud detection rates for ESCS 1, ESCS 2, ESCS 3 and ESCS 5 when compared with single classifiers and ensemble classifiers. The second-best result was ESCS 2 with the meta-classifier RF, for which the fraud detection rate was 0.8028, followed by ESCS 3 with the meta-classifier LR at 0.7785, ESCS 1 with the meta-classifier ID3 at 0.7622 and ESCS 5 with the meta-classifier MLP at 0.7520.\n\nIn conjunction with this experiment, ESCS was compared to other researchers’ works. The comparisons are shown in Table 6.\n\nESCS outperformed the rest. TPR (1)= true positive rate for minority class; TPR (0) = true positive rate for majority class.\n\nESCS was able to achieve the highest TPR (0.8841) for the minority class, and outperformed the other researchers’ models. ESCS also gave a good accuracy of 0.9837 and a TPR of 0.9839 for the majority class.\n\nESCS with NB as the meta-classifier showed great performance, and proved that ESCS could improve the fraud detection rate as it can effectively identify misclassified fraud transactions.\n\n\nConclusions\n\nNowadays, credit cards are the most common payment method because of the conveniences they provide. If credit card usage is not well-managed, it may lead to undesirable events, such as credit card frauds. Credit card frauds involve the illegal use of credit cards without the owner’s consent and cause them to suffer a financial loss.\n\nUtilising credit card transaction data is now a necessity to detect frauds. However, it would be challenging to handle credit card data because of their (i) unbalanced class distributions and (ii) overlapping classes. These characteristics also cause difficulties for general learning algorithms to detect frauds effectively.\n\nThis study proposes to address these two issues using an ESCS, strategically separating the classes and tackling the data individually at different levels to improve fraud detection rates. We compared the performance of ESCS with single bagging and boosting classifiers. The highest TPR for the minority class (frauds) was 0.8841 using ESCS with NB as the meta-classifier, which outperformed other combinations. We also compared our ESCS with previous research. The results showed that our ESCS outperformed other researchers’ works. This study proves that ESCS can improve the fraud detection rate on credit card data.\n\n\nData availability\n\nFigshare: CCFD_dataset, https://doi.org/10.6084/m9.figshare.16695616.v3.28\n\nThis project contains the following underlying data:\n\n- CCFD_dataset.xlsx (extracted credit card dataset from the original Kaggle 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\nAnalysis code available from: https://github.com/nuramirahishak/ESCS/tree/escs\n\nArchived analysis code as as time of publication: https://doi.org/10.5281/zenodo.5647747.29\n\nLicense: OSI 3.0",
"appendix": "References\n\nAhmed ZU, Ismail I, Sadiq Sohail M, et al.: Malaysian consumers’ credit card usage behavior. Asia Pac. J. Mark. Logist. 2010; 22(4): 528–544. Publisher Full Text\n\nRaju O: A Survey on Machine Learning Algorithms in Credit Card Fraud Detection.2021; vol. 25(no. 1): pp. 712–727. Reference Source\n\nPozzolo AD, Caelan O, Borgne YL, et al.: Learned Lessons in Credit Card Fraud Detection from A Practitioner Perspective. Expert Syst. Appl. 2014; 41: 4915–4928. Publisher Full Text\n\nFulmer L: Global Card Fraud Losses Reach $16.31 Billion-Will Exceed $35 Billion in 2020 According to The Nilson Report.2015. [2019, October 19].Reference Source\n\nVan Vlasselaer V, Bravo C, Caelen O, et al.: APATE: A novel approach for automated credit card transaction fraud detection using network-based extensions. Decis. Support. Syst. 2015; 75: 38–48. Publisher Full Text\n\nde Sá AGC , Pereira ACM, Pappa GL: A customised classificationalgorithm for credit card fraud detection. Eng. Appl. Artif. Intell. 2018; vol. 72: pp. 21–29. 0952-1976. Publisher Full Text\n\nHaixiang G, Yijing L, Shang J, et al.: Learning from class-imbalanced data: Review of methods and applications. Expert Syst. Appl. 2016; vol. 73: pp. 220–239. 09574174Publisher Full Text\n\nBekkar M, Djemaa HK, Alitouche TA: Evaluation Measures for Models Assessment over Imbalanced Data Sets. Journal of Information Engineering and Applications 2013; vol. 3(no.10): pp. 27–38. 2225-0506.\n\nPozzolo AD, Caelan O, Johnson RA, et al.: Calibrating Probability with Undersampling for Unbalanced Classification. 2015 IEEE Symposium Series on Computational2015; pp. 159–166. Publisher Full Text\n\nAkosa J: Predictive Accuracy: A Misleading Performance Measure for Highly Imbalanced Data. Proc. SAS Global Forum 2017; 1–12.\n\nKrawczyk B: Learning from imbalanced data: open challenges and future directions. Prog. Artif. Intell. 2016; 5: 221–232. Publisher Full Text\n\nLee H, Kim S: An overlap-sensitive margin classifier for imbalanced and overlapping data. Expert Syst. Appl. 2018; 98: 72–83. Publisher Full Text\n\nDas B, Krishnan NC, Cook DJ: Handling Class Overlap and Imbalance to Detect Prompt Situations in Smart Homes. IEEE 13th International Conference on Data Mining Workshops. 2013. Publisher Full Text\n\nQu Y, Su H, Guo L, et al.: A novel SVM modeling approach for highly imbalanced and overlapping classification. Intell. Data Anal. 2011; 15: 319–341. Publisher Full Text\n\nNapierala K, Stefanowski J: Types of minority class examples and their influence on learning classifiers from imbalanced data. J. Intell. Inf. Syst. 2016; 46: 563–597. Publisher Full Text\n\nBlaszczynski J, Stefanowski J: Neighbourhood sampling in bagging for imbalanced data. Neurocomputing 2015; 150: 529–542. Publisher Full Text\n\nLango M, Stefanowski J: Multi-class and feature selection extensions of Roughly Balanced Bagging for imbalanced data. J. Intell. Inf. Syst. 2018; 50: 97–127. Publisher Full Text\n\nHusejinovic A: Credit card fraud detection using naive Bayesian and C4.5 decision tree classifiers. Periodicals of Engineering and Natural Sciences 2020; 8(1): 1–5. http://pen.ius.edu.ba.\n\nBreiman L: Bagging Predictors. Mach. Learn. 1996; 24: 123–140. Publisher Full Text\n\nRajora S, Li D, Jha C, et al.: A Comparative Study of Machine Learning Techniques for Credit Card Fraud Detection Based on Time Variance. IEEE Symposium Series on Computational Intelligence (SSCI) 2018; 1958–1963. Publisher Full Text\n\nBreiman L: Random forests. Mach. Learn. 2001; 45: 5–32. Publisher Full Text\n\nDivakar K, Chitharanjan K: Performance Evaluation of Credit Card Fraud Transactions using Boosting Algorithms. International Journal of Electronics Communication and Computer Engineering 2019; 10: 262–270.\n\nBarahim A, Alhajri A, Alasaibia N, et al.: Enhancing the Credit Card Fraud Detection Through Ensemble Techniques. J. Comput. Theor. Nanosci. 2019; 16: 4461–4468. Publisher Full Text\n\nKalid SN, Ng KH, Tong GK, et al.: A Multiple Classifiers System for Anomaly Detection in Credit Card Data with Unbalanced and Overlapped Classes. IEEE Access 2020; 8: 28210–28221. Publisher Full Text\n\nSailusha R, Gnaneswar V, Ramesh R, et al.: Credit Card Fraud Detection Using Machine Learning. 4th International Conference on Intelligent Computing and Control Systems (ICICCS).2020. Publisher Full Text\n\nWolpert DH: Stacked generalisation. Neural Netw. 1992; 5(2): 241–259. Publisher Full Text\n\nPrabhakara E, Kumarb MN, Ponnarb K, et al.: Credit card fraud detection using boosted stacking. South Asian J. Eng. Technol 2019; 8(S1): 149–153.\n\nIshak NA, Ng K-H, Tong G-K, et al.: CCFD_dataset. figshare. Dataset. 2021. Publisher Full Text\n\nnuramirahishak: nuramirahishak/ESCS: ESCS python scripts (escs). Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "122464",
"date": "22 Jul 2022",
"name": "Yen Lung Lai",
"expertise": [
"Reviewer Expertise information security"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript studies the classification problem over the credit card transactions. In particular, in a credit card transactions data set, legitimate transactions are the majority class, whereas frauds are the minority class.\n\nThe authors proposed the enhanced stacking classifier system (ESCS) to address class distributions and overlapping issues. It was strategically designed by separating the classes and tackling the data individually at different levels to improve fraud detection rates.\n\nOverall, this manuscript is comprehensive and scientifically sound. I have some comments wish to improve the quality of it:\nIt would be good if ROC curves can be provided for different classifiers/boosting/ESCS/ for better visualization of the system performance.\n\nIt is noted that the TPR for the proposed ESCS is achievable at 0.8841 (Table 6). However, the TPR and the resultant accuracy does't outperform the other researchers' works as highlighted in Table 6. The author should elaborate more on such result for fair comparison. Maybe more explanation on why the TPR and overall accuracy are lower? Is there any tradeoff?\n\nMoreover, it seems the proposed ESCS framework can be considered as one type of the MSC (with multiple classifiers in parallel combination), proposed by Kalid et al., which only consists of two classifiers in level 1.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "158344",
"date": "25 May 2024",
"name": "Faouzia Benabbou",
"expertise": [
"Reviewer Expertise AI",
"Fraud detection using AI methods",
"NLP techniques",
"cloud computing",
"..."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper presents an interesting approach but the paper needs to be improved and some evidence needs to be provided:\nThe paper needs to be better organized, and the section headings need to be numbered.\n\nThe state of the art should be in a section by itself and should describe existing approaches and provide a rigorous analysis and comparison.\n\nThe state of art is very poor\n\nThe following refs are not to be placed in the state of the art part:\nBreiman L: Bagging Predictors. Mach. Learn. 1996; 24: 123-140. Publisher Full text Breiman, L. Random Forests. Machine Learning 45, 5-32 (2001). https://doi.org/10.1023/A:1010933404324\n\nBefore discussing a dataset, the authors should present the methodological flow and describe the purpose of each step. The methodology starts with the description of the dataset, preprocessing, learning and classification.\n\nThe effective confusion matrix should be given in table 2\n\nTo be sure that there is no overfitting, authors should provide curves representing the Difference between the empirically observed performance loss on the training data and that predicted from the test data (accuracy and loss model).\n\nThe authors consider that any transaction that is classified as \"fraud\" is well classified in the first step while it can be a false alarm and in the financial field false alarms must be minimized as consequences are huge and more costly.\n\nEven after the dataset cutting it can still have imbalanced problem in some folds because the minority class is small, the authors must explain and show that the split parts do not suffer from imbalanced data\n\nEven if the performance is interesting, what about the response time of this system if the detection is in real time\n\nThe use of oversampling improve greatly the classification you can see this ref: Sadgali I. et al (2021 1).\n\nThe Paper needs proof Reading\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/11-71
|
https://f1000research.com/articles/9-712/v1
|
16 Jul 20
|
{
"type": "Case Report",
"title": "Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome",
"authors": [
"Satoshi Karasawa",
"Taka-aki Nakada",
"Naoto Mori",
"Michiko Daimon",
"Hideyuki Miyauchi",
"Tetsuya Kanai",
"Hiroyuki Takano",
"Yoshio Kobayashi",
"Shigeto Oda",
"Satoshi Karasawa",
"Naoto Mori",
"Michiko Daimon",
"Hideyuki Miyauchi",
"Tetsuya Kanai",
"Hiroyuki Takano",
"Yoshio Kobayashi",
"Shigeto Oda"
],
"abstract": "Introduction: Propofol infusion syndrome (PRIS) is rare but a potentially lethal adverse event. The pathophysiologic mechanism is still unknown. Patient concerns: A 22-year-old man was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings, acute kidney injury, hyperkalemia and severe rhabdomyolysis. Diagnosis and interventions: The patient was transferred to our intensive care unit (ICU) on suspicion of PRIS. Administration of noradrenaline and renal replacement therapy and fasciotomy for compartment syndrome of lower legs due to PRIS-rhabdomyolysis were performed. Outcomes: The patient gradually recovered and was discharged from the ICU on day 30. On day 37, he had repeated sinus bradycardia with pericardial effusion in echocardiography. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle. Electron microscopic investigation of endomyocardial biopsy on day 75 revealed mitochondrial myelinization of the cristae, which indicated mitochondrial damage of cardiomyocytes. He was discharged without cardiac abnormality on day 192. Conclusions: Mitochondrial damage in both morphological and functional aspects was observed in the present case. Sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.",
"keywords": [
"mitochondria",
"arrhythmia",
"cardiac failure",
"Propofol"
],
"content": "Abbreviations\n\nPRIS, propofol infusion syndrome; 18F-FDG PET,18F-fluorodeoxyglucose positron emission tomography.\n\n\nIntroduction\n\nPropofol is extensively used in the intensive care units (ICU) for sedation1. Propofol infusion syndrome (PRIS) is widely recognized as an adverse event of this commonly used drug, but is rare and potentially lethal2. The pathophysiologic mechanism is still unknown. However, mitochondrial damage is suggested to be a potential pathogenesis mechanism. Here we report a severe case of PRIS with evidence of mitochondrial damage in both morphological and functional aspects.\n\n\nCase presentation\n\nA 22-year-old man, who was a healthy university student with Japanese ancestry without preexisting medical and family history, experienced muscle weakness and was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered via a peripheral venous catheter for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings (ST elevation in II, III, and aVF). Blood test revealed acute kidney injury, hyperkalemia and severe rhabdomyolysis (serum creatinine phosphokinase 271,700 IU/L, normal range 68-287 IU/L). He was transferred to our ICU on suspicion of PRIS by excluding other diagnoses. Administration of noradrenaline via a central venous catheter (0.3 µg/kg/min) and hemodialysis were initiated, and fasciotomy by orthopedic surgeons under general anesthesia without propofol was required for compartment syndrome of lower legs due to PRIS-rhabdomyolysis. Noradrenaline was gradually reduced and terminated on day 15. He gradually recovered from cardiac and renal dysfunction according to echocardiography and blood tests and was discharged from the ICU on day 30. On day 37, he repeatedly presented sinus bradycardia and right bundle branch block in continuous electrocardiogram monitoring, eventually requiring temporary pacing via the intracardiac placement of a pacing wire, with a finding of pericardial effusion on echocardiography. Detailed examination including cardiac 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was conducted to evaluate whether these late-phase cardiac events were related to PRIS. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle (Figure 1). Electron microscopic investigation of the endomyocardial biopsy, which was taken on day 75 to examine the cause of cardiac dysfunction, revealed abnormal findings in the mitochondria of the cardiomyocytes, including myelinization of the cristae (Figure 2). Since weakness of respiratory muscles and extremities muscles needed mechanical ventilation and rehabilitation, he was treated in the hospital for another 3 months．He was taken off the ventilator and transferred to another hospital on day 192 due to persisting muscle weakness, but with normal cardiac function without arrhythmia. Three-year follow-up revealed that he had normal cardiac function with normal activities of daily living.\n\n18F-fluorodeoxyglucose positron emission tomography showed heterogeneous 18F-FDG uptake in left ventricle.\n\nElectron microscopy revealed mitochondrial myelinizations of the cristae in cardiomyocyte. Arrows indicate cardiomyocytes with the mitochondrial injury. Scale bar: 1 µm.\n\n\nDiscussion and conclusions\n\nMitochondrial damage is suggested as a potential pathogenesis of PRIS2–4. Mitochondrial damage was observed as a morphological finding in an electron microscopic evaluation of the heart in an autopsy case of PRIS5. Similarly, mitochondrial damage was observed in the endomyocardial biopsy two months after the onset in the present case. Mitochondrial damage can also be detected as a functional impairment of fatty acid utilization with alternatively increased glucose utilization6. The uptake of a glucose analog (18F-FDG) in left ventricle on day 67 (Figure 1) in the present case implies a shift in the energy substrate of cardiomyocytes from fatty acid to glucose, suggesting mitochondrial damage. To the best of our knowledge, this is the first to report a case of PRIS with evidence of mitochondrial damage in both morphological and functional aspects, which is the strength of this case report. The evidence of mitochondrial damage by 18F-FDG PET and electron microscopic investigation was not repeatedly evaluated during the time-course but a single time-point (18F-FDG PET on day 67 and endomyocardial biopsy 75), which is a potential limitation. Since the mitochondrial damage was detected 2 month later after PRIS onset, sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.\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 and clinical images was obtained from the patient.",
"appendix": "References\n\nJacobi J, Fraser GL, Coursin DB, et al.: Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002; 30(1): 119–141. PubMed Abstract | Publisher Full Text\n\nKrajcova A, Waldauf P, Andel M, et al.: Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015; 19: 398. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWolf A, Weir P, Segar P, et al.: Impaired fatty acid oxidation in propofol infusion syndrome. Lancet. 2001; 357(9256): 606–607. PubMed Abstract | Publisher Full Text\n\nBranca D, Roberti MS, Lorenzin P, et al.: Influence of the anesthetic 2,6-diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol. 1991; 42(1): 87–90. PubMed Abstract | Publisher Full Text\n\nVollmer JP, Haen S, Wolburg H, et al.: Propofol Related Infusion Syndrome: Ultrastructural Evidence for a Mitochondrial Disorder. Crit Care Med. 2018; 46(1): e91–e94. PubMed Abstract | Publisher Full Text\n\nVandanmagsar B, Warfel JD, Wicks SE, et al.: Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle. Cell Rep. 2016; 15(8): 1686–1699. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "74264",
"date": "12 Nov 2020",
"name": "Susanne Haen",
"expertise": [
"Reviewer Expertise Pathology",
"Neuroscience",
"Electron Microscopy"
],
"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 concentration of several short-chain acylcarnitines in the patient's blood is missing.\nFurthermore,the authors showed an electron microscopical image of mitochondria in the heart muscle with \"myelinization of the cristae\" but they don't write anything about the pathological backround, the interpretation is missing. In our article (Vollmer et al.) the amorphous figures associated with mitochondria in the heart muscle could be interpreted as free fatty acids but they look completely different than the myelinized structures in the mitochondria in the article of Karasawa et al.\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? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": [
{
"c_id": "7583",
"date": "20 Jan 2022",
"name": "Satoshi Karasawa",
"role": "Author Response",
"response": "Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic. Unfortunately, we have no samples available to measure short-chain acylcarnitines. According to the comments, we added the sentences to improve the manuscript. Added (Case presentation): Electron microscopic investigation of the endomyocardial biopsy, which was taken on day 75 to examine the cause of cardiac dysfunction, revealed abnormal findings in the mitochondria of the cardiomyocytes, including myelinization of the cristae (Figure 2), which was interpreted as mitochondrial damage. Previous (Discussion and Conclusions):: Mitochondrial damage was observed as a morphological finding in an electron microscopic evaluation of the heart in an autopsy case of PRIS 5 . Similarly, mitochondrial damage was observed in the endomyocardial biopsy two months after the onset in the present case. Revised (Discussion and Conclusions): Mitochondrial damage was observed as a morphological finding in an electron microscopic evaluation of the heart in an autopsy case of PRIS 5 . We found myelinization of the cristae in cardiomyocyte on day 75; however, similar findings were not observed in postmortem electron microscopical image of mitochondria of PRIS in the previous report5. Different clinical course and timepoints may alter mitochondrial conditions. The autopsy study measured blood levels of short-chain acylcarnitines, while we have no blood sample available for the measurement. Further studies measuring blood levels of short-chain acylcarnitines would strengthen the case results."
}
]
},
{
"id": "74771",
"date": "27 Nov 2020",
"name": "Anja Karlstaedt",
"expertise": [
"Reviewer Expertise Cardiology",
"Metabolism",
"Systems Biology",
"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\nKarasawa et al. present a case report titled \"Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome.\" The authors describe the case of a 22-year-old man of Japanese descent who developed a propofol infusion syndrome (PRIS) as a complication of his treatment of Guillain-Barre syndrome. PRIS is a rare syndrome with an unknown pathophysiologic mechanism, lack of specific signs and symptoms, and high mortality. Together these factors pose a challenge for clinicians to identify patients with potential PRIS and to provide treatment. The present case report may help other clinicians manage a patient with possible PRIS and allow future studies to elucidate the underlying molecular mechanisms causing the syndrome. The authors present their case clearly and concisely. However, the report has several shortcomings, which should be addressed in a revision.\nMajor concerns\nThe authors need to provide quantifications for the 18F-FDG PET imaging, including how they normalized their counts (e.g., brain, blood glucose level before and after the imaging). The PET image lacks a scale.\n\nAdditional information regarding the endomyocardial biopsy is required. The authors should comment if they observed apoptotic myocytes, which stages of morphological stages of mitochondrial degeneration they found (e.g., A to D), and potentially provide quantification.\n\nThe authors indicate in their introduction that \"mitochondrial damage is suggested to be a potential pathogenesis mechanisms.\" Further, in the discussion and conclusions, the authors suggest that \"Mitochondrial damage can also be detected as a functional impairment of fatty acid utilization with alternatively increased glucose utilization [Ref 6].\" Readers who are less familiar with PRIS or cardiac metabolism would benefit from a brief description of how propofol impairs carnitine palmitoyl transport activities and cardiac calcium dynamics, potentially affecting the oxidation of fatty acids. The shift in energy-providing substrates is an essential pathophysiological aspect of the case report and, in general, cardiac stress response. Additional descriptions and references will help readers to follow the author's rationale.\n\nThe authors need to differentiate their case presentation between mitochondrial damage at the structural level as supported by the histology and functional changes due to metabolic remodeling. Metabolic remodeling in the heart can precede structural changes (for reference see: References 1-5). 18F-FDG PET imaging shows increased glucose utilization in the heart on day 67, and the authors provide evidence for mitochondrial structural damage at day 75. The authors correctly conclude that these results imply a shift from predominant fatty acid oxidation to glucose. However, the data are insufficient to conclude that these flux changes occur due to mitochondrial damage or pharmacologic modulation of key regulatory enzymes and transporters, without additional time points.\n\nThe authors state: \"The evidence of mitochondrial damage by 18F-FDG PET […].\" 18F-FDG-PET imaging does not determine mitochondrial damage but measures glucose uptake. Please revise (for example: \"The evidence of increased glucose uptake and mitochondrial damage by […].\")\nMinor remarks and questions:\nDid the authors observe any changes in the blood glucose level or glucose tolerance of the patient?\n\nThe authors may consider further quantification of mitochondrial degeneration in their tissue sample using markers for autophagy and apoptosis, e.g., BNIP3, FOXO3a, BCL-2, or OPA1.\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? 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 case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "7584",
"date": "20 Jan 2022",
"name": "Satoshi Karasawa",
"role": "Author Response",
"response": "Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic. 1. The authors need to provide quantifications for the 18F-FDG PET imaging, including how they normalized their counts (e.g., brain, blood glucose level before and after the imaging). The PET image lacks a scale.l. Response: Thank you for the comment. According to the comment, we revised the sentence and scale. Added (Case presentation): Detailed examination including cardiac 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was conducted to evaluate whether these late-phase cardiac events were related to PRIS. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle with the maximum standardized uptake value (SUV) of 3.97. Blood glucose level before and after imaging was 90 mg/dL. Added (Figure and Figure legends): I added scale bar to the Figure1. Figure1. 18F-fluorodeoxyglucose positron emission tomography. 18F-fluorodeoxyglucose positron emission tomography showed heterogeneous 18F-FDG uptake in left ventricle. Scale bar: 5cm 2. Additional information regarding the endomyocardial biopsy is required. The authors should comment if they observed apoptotic myocytes, which stages of morphological stages of mitochondrial degeneration they found (e.g., A to D), and potentially provide quantification. Response: Thank you for the comment. According to the comment, we added a sentence in the Case presentation section. Since the sample preparation for electron microscope images could affect the morphological stages, we assume that we could not accurately estimate the morphological stage of mitochondrial degeneration. Added (Case presentation): Electron microscopic investigation of the endomyocardial biopsy, which was taken on day 75 to examine the cause of cardiac dysfunction, revealed abnormal findings in the mitochondria of the cardiomyocytes, including myelinization of the cristae ( Figure 2), which was interpreted as mitochondrial damage. In addition, apoptotic myocytes were not observed. 3. The authors indicate in their introduction that \"mitochondrial damage is suggested to be a potential pathogenesis mechanisms.\" Further, in the discussion and conclusions, the authors suggest that \"Mitochondrial damage can also be detected as a functional impairment of fatty acid utilization with alternatively increased glucose utilization [Ref 6].\" Readers who are less familiar with PRIS or cardiac metabolism would benefit from a brief description of how propofol impairs carnitine palmitoyl transport activities and cardiac calcium dynamics, potentially affecting the oxidation of fatty acids. The shift in energy-providing substrates is an essential pathophysiological aspect of the case report and, in general, cardiac stress response. Additional descriptions and references will help readers to follow the author's rationale Response: Thank you for the comment. According to the comment, we added a reference and sentences in the Discussion and Conclusions. Added (Discussion and Conclusions): : Propofol is known to inhibit the effects of carnitine palmityl transferase 1 (CPT 1), which transports long-chain fatty acids into the mitochondria3. Thus, propofol potentially impairs carnitine palmitoyl transport activities and cardiac calcium dynamics, affecting the oxidation of fatty acids. 4. The authors need to differentiate their case presentation between mitochondrial damage at the structural level as supported by the histology and functional changes due to metabolic remodeling. Metabolic remodeling in the heart can precede structural changes (for reference see: References 1-5). 18F-FDG PET imaging shows increased glucose utilization in the heart on day 67, and the authors provide evidence for mitochondrial structural damage at day 75. The authors correctly conclude that these results imply a shift from predominant fatty acid oxidation to glucose. However, the data are insufficient to conclude that these flux changes occur due to mitochondrial damage or pharmacologic modulation of key regulatory enzymes and transporters, without additional time points. Response: Thank you for the comment. According to the comment, we added sentences in the Discussion and Conclusions. Added (Discussion and Conclusions): The evidence of mitochondrial damage by 18F-FDG PET and electron microscopic investigation was not repeatedly evaluated during the time-course but a single time-point (18F-FDG PET on day 67 and endomyocardial biopsy 75), which is a potential limitation. Additional timepoints data in future studies could reveal that shifts from predominant fatty acid oxidation to glucose occur due to mitochondrial damage or pharmacologic modulation of key regulatory enzymes and transporters. 5. The authors state: \"The evidence of mitochondrial damage by 18F-FDG PET […].\" 18F-FDG-PET imaging does not determine mitochondrial damage but measures glucose uptake. Please revise (for example: \"The evidence of increased glucose uptake and mitochondrial damage by […].\") Response: According to the comment, we revised the sentence. Previous (Discussion and Conclusions): The evidence of mitochondrial damage by 18F-FDG PET and electron microscopic investigation was not repeatedly evaluated during the time-course but a single time-point ( 18F-FDG PET on day 67 and endomyocardial biopsy 75), which is a potential limitation. Since the mitochondrial damage was detected 2 month later after PRIS onset, sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration. Revised (Discussion and Conclusions): The evidence of increased glucose uptake by 18F-FDG PET and mitochondrial damage by electron microscopic investigation was not repeatedly evaluated during the time-course but a single time-point ( 18F-FDG PET on day 67 and endomyocardial biopsy 75), which is a potential limitation. Since the mitochondrial damage was detected 2 month later after PRIS onset, sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration. Minor concerns 1. Did the authors observe any changes in the blood glucose level or glucose tolerance of the patient? Response: According to the comment, we added the sentences. Added (Case presentation): Detailed examination including cardiac 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was conducted to evaluate whether these late-phase cardiac events were related to PRIS. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle with the maximum standardized uptake value (SUV) of 3.97. Blood glucose level before and after imaging was 90 mg/dL. Added: We observed no significant changes in the blood glucose and glucose tolerance of the patient during his hospital stay. 2. The authors may consider further quantification of mitochondrial degeneration in their tissue sample using markers for autophagy and apoptosis, e.g., BNIP3, FOXO3a, BCL-2, or OPA1. Response: Thank you for the comment. Unfortunately, we have no tissue sample available for further measurements."
}
]
}
] | 1
|
https://f1000research.com/articles/9-712
|
https://f1000research.com/articles/11-67/v1
|
20 Jan 22
|
{
"type": "Method Article",
"title": "Synthetic time series data generation for edge analytics",
"authors": [
"Subarmaniam Kannan"
],
"abstract": "Background: Internet of Things (IoT) edge analytics enables data computation and storage to be available adjacent to the source of data generation at the IoT system. This method improves sensor data handling and speeds up analysis, prediction, and action. Using machine learning for analytics and task offloading in edge servers could minimise latency and energy usage. However, one of the key challenges in using machine learning in edge analytics is to find a real-world dataset to implement a more representative predictive model. This challenge has undeniably slowed down the adoption of machine learning methods in IoT edge analytics. Thus, the generation of realistic synthetic datasets can leverage the need to speed up methodological use of machine learning in edge analytics. Methods: We create synthetic data with features that are like data from IoT devices. We use an existing air quality dataset that includes temperature and gas sensor measurements. This real-time dataset includes component values for the Air Quality Index (AQI) and ppm concentrations for various polluting gases. We build a JavaScript Object Notation (JSON) model to capture the distribution of variables and the structure of this real dataset to generate the synthetic data. Based on the synthetic dataset and original dataset, we create a comparative predictive model. Results: Analysis of synthetic dataset predictive model shows that it can be successfully used for edge analytics purposes, replacing real-world datasets. There is no significant difference between the real-world dataset compared the synthetic dataset. The generated synthetic data requires no modification to suit the edge computing requirements. Conclusions: The framework can generate representative synthetic datasets based on JSON schema attributes. The accuracy, precision, and recall values for the real and synthetic datasets indicate that the logistic regression model is capable of successfully classifying data.",
"keywords": [
"Synthetic data generation",
"Internet of Things",
"edge analytics",
"predictive model",
"machine learning"
],
"content": "Introduction\n\nThe widespread adoption of the Internet of Things (IoT) in business and industry has resulted in significant investment in advanced applications development (Brous et al., 2020). These applications focus on increasing efficiency and cost reduction while speeding up the analytic process at receiving ends. However, initial IoT data generation and dependence on cloud-based data storage and data processing have limited the success with IoT applications. “Roughly 10% of enterprise-generated data is processed outside of an established centralised data centre or cloud,” according to Gartner. By 2025, it is predicted that this number would have grown to 75% (Van der Meulen, 2018).\n\nAs a result, Edge Computing (EC) is emerging as a key enabler technology for network edge-based analytics and real-time decision-making. Edge computing places processing and analytics capability close to the source of the data. While extracting high-level data from the raw sensory input, this strategy reduces network latency. Integration of Machine Learning (ML) capabilities into EC has enabled sensor-based application specific analytics at the IoT network edge. Due to technological advancements in computer processor power, energy efficiency, memory capacity, and device size downsizing, machine learning computation can now be performed at edge nodes (Murshed et al., 2022).\n\nThe development of ML-based edge analytics for IoT applications is unlike that of traditional machine learning due to the hardware limitations and lack of sensory data availability associated with ML-based edge analytics (Li et al., 2021). Finding real-world datasets that reflect sensory data for a prediction model is one of the troublesome issues in ML-based edge analytics development (Chen et al., 2020). This issue is undeniably hampering the rapid adoption of machine learning methods in IoT Edge analytic integration.\n\nThus, realistic synthetic dataset generation can leverage the need to speed up the methodological use of machine learning in edge analytics. Synthetic data is information that is artificially designed to represent real-world events (Nikolenko, 2019). Researchers have used various techniques such as stochastic process (Salim et al., 2018), rule-based data generation (Jeske et al., 2005) and deep generative model (Alzantot et al., 2017) to generate synthetic data for many applications (Anderson et al., 2014). Because of privacy and legality concerns, data science has given rise to synthetic data. Synthetic data has been widely used to supplement the ever-increasing demand for data science to predict various global business and environmental phenomena (Howe et al., 2017). When a need for previously unheard-of real-world datasets arises, the importance of synthetic data increases to criticality. Yet, the use of synthetic datasets has become difficult when compounded by the need for privacy preservation. Due to a scarcity of genuine datasets, medical researchers have been employing synthetic data to evaluate medical applications in conditional and control environments (Azizi et al., 2021). Similarly, self-driving vehicle re-identification technology uses randomized synthetic data as a precursor to training vehicles (Tang et al., 2019).\n\nThe scarcity of getting accurate IoT generated datasets to represent localized real-world environments and the inaccuracy of pre-defined or public repository datasets has driven IoT researchers to generate synthetic data to cater to their unique requirements (Sengupta & Chinnasamy, 2020; Tazrin, 2021; Zualkernan et al., 2021).\n\nThere are several benefits that the use of synthetic data brings when compensating for unavailable real-world data. Firstly, the advent of personal and community privacy advocacy has limited many developers and researchers in using real datasets (Oh et al., 2020). The creation of synthetic data that represents details of real-world data, including distributions, non-linear relationships, and noise, can eliminate legal issues (Tucker et al., 2020). Instead of using costly real-world data to generate a predictive model, synthetic data are able to cater to various possible desired predictive events found in real datasets (Jordon et al., 2018).\n\nThe remainder of the paper is structured as follows. Section 2 discusses related work in the area of synthetic data creation. Section 3 discusses the JSON-based synthetic data generation framework. Section 4 presents the generated synthetic datasets and the results of the synthetic data validation experiment. Section 5 outlines the conclusions.\n\n\nRelated work\n\nAccording to Coimbra et al. (2020), the difficulty in training the machine learning model for detection and classification with suitable datasets that cover all the possibilities of a domain may be expensive and could be associated with privacy concerns. Thus, synthetic data offers a potential answer in terms of lowering the cost of data acquisition while also addressing data privacy concerns.\n\nThe bulk of synthetic data creation methods rely on extracting properties from existing real-world datasets. These extracted features from a real dataset are utilised to create a new dataset. Several criteria are used as guidelines to generate synthetic data. Deep Neural Network (DNN)-based methods include Auto-Encoders (AE) and Generative Adversarial Networks (GAN) (Frid-Adar et al., 2018).\n\nHowever, Torres (2018) point out that the suggested generation process's pattern identification phase states that after determining (quantitatively) the impact of each feature, the dataset columns are ordered according to how important they are. Priority may be assigned in the following order: most influential to least influential, or vice versa. This strategy may not be optimal or time-efficient, and so may have a detrimental influence on training and processing durations if a computationally expensive characteristic is checked at the start of the cue.\n\nHowever, some researchers create synthetic data based using actual data formats such as Comma-Separated Values (CSV), Java Script Object Notation (JSON), and Extensible Markup Language (XML). Anderson et al. (2014) developed and built a Hadoop-based synthetic IoT data creation system capable of producing vast amounts of data. Using the Document Type Definition (DTD) and the recreation synthesis set, this system extracts data structures from IoT XML data. Through different XML data extensions, this modular system supports many statistical distributions.\n\nJSON data types are human-readable data and may represent metadata and computer-readable data (Sun et al., 2020). The JavaScript Language comprises pre-defined data structures, such as arrays that provide order lists and objects that represent name-value pairs. JSON metadata offer an effective method to examine the structure and variables of any data file, particularly a big dataset. In contrast to XML, which is a native format of the JavaScript language, JSON-based datasets are simple to read and represent a data exchange language. Many computer languages such as C++, C#, Cold Fusion, Java, Perl, PHP, Python and Ruby support it for online data integration.\n\nThe features of IoT data are critical in the creation and structure of synthetic data and can be classified based on the method through which the data is collected. Applications such as IoT-based digital healthcare systems (Ed-daoudy & Maalmi, 2019) and autonomous vehicle monitoring systems (Kavitha & Ravikumar, 2020), generate huge amounts of data in continuous streams. Additionally, it is important to consider how the massive data was gathered and stored away from IoT and edge devices. These massive databases are processed and analysed in order to forecast long-term business trends. Streaming datasets, on the other hand, require rapid pre-processing and analytics in order to extract immediate and relevant information for a speedy decision, like in the autonomous vehicle example (Elsaleh et al., 2020). Time-series data is used to generate a large quantity of streaming IoT data (Kumar et al., 2020). Data from streaming IoT devices is collected and analysed depending on the time it was generated. The ability to synchronise time across a pool of IoT devices spread over a large monitoring environment will be critical in evaluating the quality of this data (Ferrari et al., 2020).\n\n\nMethods\n\nThe primary objective of this synthetic data creation is to provide an experimental framework that may train a machine learning prediction model. The framework can create correct JSON schema characteristics based on synthetic datasets. This section introduces the IoT synthetic data creation framework, which is divided into two stages. The first stage involves extracting structure and variables from the original time series dataset in comma-separated values (.CSV) format. In the second stage, the extracted structure and variables from the original datasets are used to develop and construct synthetic CSV datasets. Figure 1 shows a schematic diagram that depicts the framework for generating synthetic data.\n\nCSV, Comma-Separated Values.\n\nThe original dataset for this experiment (Air Quality Data in India 2015-2020) was obtained from the Kaggle dataset repository (see Underlying data). We choose this dataset based on its data format (CSV) and because it is publicly available online. The dataset contains air quality data and AQI (Air Quality Index) for different stations in 26 Indian cities, taken on an hourly basis. The dataset contains different air quality indices that are rated in parts per million (ppm) as satisfactory (80-99), moderate (100-199), poor (200-299), and very poor (300-400). These categories reflect the quality of the air based on data collected from dataset and will be utilised as predictive components in the trained model.\n\nThe dataset is formatted in a CSV file with several columns that influence the type of categories that the air quality will be, such as –StationId” for the station where the sensors were placed, “PM2.5 and PM10” for the number of particles with 2.5 micrometres and 10 micrometres, and the rest are the concentration of chemicals and gases in the air that will influence the AQI. Table 1 shows the data components of the AQI dataset.\n\nThe CSV file containing the original AQI dataset is converted to JSON using the freely available online CSV to JSON parser, CSVJSON (Drapeau et al., 2014). After that, the output is saved as a text file (csvjson1.txt). The original dataset's JSON output contains arrays of data objects but no structure or syntax. To enable the structure and variables to be identified, the JSON file is converted to JSON Schema using the freely available Online JSON to JSON Schema Converter (Liquid Technologies Limited, 2001). The JSON schema output demonstrates the syntax and structure's accuracy and the file's entire structure and variable components. The JSON Schema in Figure 2 is derived from the JSON file containing the original AQI dataset.\n\nPM2.5, number of particles that are 2.5 micrometres; PM10, number of particles that are 10 micrometres; NO, nitric oxide; NO2, nitric dioxide; NOx, nitrogen oxides; NH3, ammonia; CO, carbon monoxide; SO2, sulphur dioxide; O3, ozone.\n\nOnce the variable components and structure of the AQI dataset JSON schema have been identified, they are mapped and written into the Python Faker (version 8.1.2) data generator application (Faraglia, 2017). The Faker data generator application generates 240000 synthetic data records in CSV format for this experiment. We limited the size to facilitate the extraction and processing of the output structure and variables.\n\nThe synthetic dataset's CSV file is then converted to JSON using the online CSV to JSON parser. After that, the output is saved as a text file (csvjson2.txt). The next step is to use the Online-JSON-to-JSON schema-converter to convert the JSON structured text file to JSON Schema.\n\nThe JSON schema for this synthetic dataset is verified by ensuring that the structure and variable elements match the JSON schema for the actual AQI dataset. This is the first step in the validation process, and it is used to determine the quality of the generated synthetic dataset. The JSON Schema structure for the generated synthetic dataset is depicted in Figure 3; see Underlying data (Kannan, 2021a).\n\nPM2.5, number of particles that are 2.5 micrometres; PM10, number of particles that are 10 micrometres; NO, nitric oxide; NO2, nitric dioxide; NOx, nitrogen oxides; NH3, ammonia; CO, carbon monoxide; SO2, sulphur dioxide; O3, ozone; AQI, Air Quality Index.\n\nFor this experiment, accuracy will be measured as the proportion of accurate predictions of the given air quality index. Precision will be determined by the proportion of accurate classifications. For example, how many of the air quality indicators in the 'poor' category were properly classified? To recall, it will be evaluating the model itself on how much of the data was properly classified given the air quality index. The ideal model would strive for high accuracy, precision, and recall value.\n\n\nResults\n\nThe full analysis code is available in Software availability (Kannan, 2021b). To open the files, use Jupyter. Python Faker generated approximately 240000 synthetic data points for this experiment purpose. The first visible comparison is based on the JSON Schema for the original dataset and the JSON Schema for the synthetic dataset, both of which appear to be quite precise in matching the same structure and variable components. We further validated our experimental approach by training a machine learning model to predict the four air quality categories specified in the dataset using both the actual AQI and a synthetic dataset.\n\nThe Python Scikit Learn library (Pedregosa et al., 2011) is used to train the both datasets using the Logistic Regression machine learning model. Logistic Regression appears to be the optimal machine learning model because it accounts for the possibility that the given condition or variable determines the air quality categories. For instance, if the air quality index (AQI) and other variables are between 80 and 99, the air quality is considered satisfactory.\n\nThe model's performance characteristics, such as accuracy, precision, and recall, vary according to the AQI dataset used. The effectiveness of the Linear Regression model in predicting both real and synthetic AQI datasets is demonstrated in Table 2. The synthetic dataset appears to outperform the real dataset by 1.03 percent; this difference may be due to the nature of the dataset that we did not remove the missing data. The synthetic dataset performs slightly better than the original dataset because the data is nearly identical to the original, and the original dataset appears to contain an error in which some rows are incomplete. This incomplete data is due to sensor failure at one of the stations that caused partial recording. A confusion matrix is constructed to explain the classification model's performance on the two datasets. Nevertheless, as demonstrated by the confusion matrix, the model is effective at classification. The confusion matrix performance of the classification model is shown in Figure 4 for both the original AQI and synthetic datasets.\n\n\nConclusions\n\nIn this paper, we present the synthetic data generation framework and its experimental results. Based on JSON schema attributes, the framework can produce correct synthetic datasets. We use both the original and synthetic datasets to train the machine learning model, in addition to early schema validation. The logistic regression model appears to be capable of successfully handling the classification process, as the accuracy, precision, and recall scores for both the real and synthetic datasets were approximately 98 percent. A predictive comparison model is developed utilising synthetic and original datasets based on the benchmark dataset. Analysis of the synthetic dataset predictive model shows that it can be successfully deployed to edge analytics to replace real-world datasets. There is no significant difference between real-world datasets compared to the synthetic dataset.\n\n\nData availability\n\nThe Air Quality Data in India (2015-2020) dataset used in this study is freely available on Kaggle: https://www.kaggle.com/rohanrao/air-quality-data-in-india. Access requires free registration to Kaggle and agreement to the terms of use.\n\nZenodo: Synthetic time series data generation for edge analytics. https://doi.org/10.5281/zenodo.5673924 (Kannan, 2021a).\n\nThis project contains the following underlying data:\n\n- Json Schema for Original Datasets.docx (JSON Schema showing original sensors data variables).\n\n- Json Schema for Synthetic Dataset.txt (JSON Schema showing generated synthetic data variables).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nSoftware availability\n\nSource code available from: https://github.com/Subar1/synthetic/tree/1.0\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.5726027 (Kannan, 2021b)\n\nLicense: MIT",
"appendix": "References\n\nAlzantot M, Chakraborty S, Srivastava M: Sensegen: A deep learning architecture for synthetic sensor data generation. 2017 IEEE International Conference on Pervasive Computing and Communications Workshops (PerCom Workshops). 2017; 188–193.\n\nAnderson JW, Kennedy KE, Ngo LB, et al.: Synthetic data generation for the internet of things. Proceedings - 2014 IEEE International Conference on Big Data, IEEE Big Data 2014. 2014. Publisher Full Text\n\nAzizi Z, Zheng C, Mosquera L, et al.: Can synthetic data be a proxy for real clinical trial data? A validation study. BMJ Open. 2021; 11(4): e043497. PubMed Abstract | Publisher Full Text\n\nBrous P, Janssen M, Herder P: The dual effects of the Internet of Things (IoT): A systematic review of the benefits and risks of IoT adoption by organizations. International Journal of Information Management. 2020; 51: 101952. Publisher Full Text\n\nChen L, Xu Y, Lu Z, et al.: IoT Microservice Deployment in Edge-cloud Hybrid Environment Using Reinforcement Learning. IEEE Internet of Things Journal. 2020. Publisher Full Text\n\nCoimbra A, Neto C, Ferreira D, et al.: Review of Trends in Automatic Human Activity Recognition in Vehicle Based in Synthetic Data. Lecture Notes in Computer Science (Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 12490 LNCS. 2020. Publisher Full Text\n\nEd-daoudy A, Maalmi K: A new Internet of Things architecture for real-time prediction of various diseases using machine learning on big data environment. Journal of Big Data. 2019; 6(1): 104. Publisher Full Text\n\nElsaleh T, Enshaeifar S, Rezvani R, et al.: IoT-Stream: A Lightweight Ontology for Internet of Things Data Streams and Its Use with Data Analytics and Event Detection Services. Sensors. 2020; 20(4): 953. PubMed Abstract | Publisher Full Text\n\nFaraglia D; O. Contributors: Faker [Computer software]. 2017, October 17. Reference Source\n\nFerrari P, Bellagente P, Depari A, et al.: Evaluation of the impact on industrial applications of NTP Used by IoT devices. 2020 IEEE International Workshop on Metrology for Industry 4.0 IoT. 2020; 223–228. Publisher Full Text\n\nFrid-Adar M, Klang E, Amitai M, et al.: Synthetic data augmentation using GAN for improved liver lesion classification. 2018 IEEE 15th International Symposium on Biomedical Imaging (ISBI 2018). 2018; 289–293. Publisher Full Text\n\nHowe B, Stoyanovich J, Ping H, et al.: Synthetic data for social good. ArXiv Preprint ArXiv:1710.08874. 2017.\n\nJeske DR, Samadi B, Lin PJ, et al.: Generation of synthetic data sets for evaluating the accuracy of knowledge discovery systems. Proceedings of the Eleventh ACM SIGKDD International Conference on Knowledge Discovery in Data Mining. 2005; 756–762.\n\nKannan S: Synthetic time series data generation for edge analytics (Version 2). Zenodo. 2021a. Publisher Full Text\n\nKannan S: Subar1/synthetic: Synthetic Data Generation. Zenodo. 2021b. Publisher Full Text\n\nKavitha D, Ravikumar S: Designing an IoT based autonomous vehicle meant for detecting speed bumps and lanes on roads. Journal of Ambient Intelligence and Humanized Computing. 2020; 12(7): 7417–7426. Publisher Full Text\n\nKumar R, Kumar P, Kumar Y: Time Series Data Prediction using IoT and Machine Learning Technique. Procedia Computer Science. 2020; 167: 373–381. Publisher Full Text\n\nLi W, Chai Y, Khan F, et al.: A Comprehensive Survey on Machine Learning-Based Big Data Analytics for IoT-Enabled Smart Healthcare System. Mobile Networks and Applications. 2021; 26(1): 234–252. Publisher Full Text\n\nLiquid Technologies Limited: Free Online JSON to JSON Schema Converter. 2001. Reference Source\n\nDrapeau M, Bluemle F, Idowu A: 2014. Reference SourceReference Source\n\nMurshed MGS, Murphy C, Hou D, et al.: Machine Learning at the Network Edge: A Survey. ACM Computing Surveys. 2022; 54(8): 1–37. Publisher Full Text\n\nNikolenko S: Synthetic data for deep learning. 2019. Reference Source\n\nPedregosa F, Varoquaux G, Gramfort A, et al.: Scikit-learn: Machine learning in Python. The Journal of Machine Learning Research. 2011; 12: 2825–2830.\n\nSalim OM, Dorrah HT, El-Kahawy MA: A novel algorithm to generate synthetic data for continuous-state stationary stochastic process (wind data application). 2018 Twentieth International Middle East Power Systems Conference (MEPCON). 2018; 333–338.\n\nSun C, Zeng X, Sun C, et al.: Research and application of data exchange based on JSON. Proceedings of 2020 Asia-Pacific Conference on Image Processing, Electronics and Computers, IPEC 2020. 2020; 349–355. Publisher Full Text\n\nTang Z, Naphade M, Birchfield S, et al.: PAMTRI: Pose-Aware Multi-Task Learning for Vehicle Re-Identification Using Highly Randomized Synthetic Data. 2019; (pp. 211–220).\n\nTorres DG: Generation of Synthetic Data with Generative Adversarial Networks. 2018. Reference Source\n\nvan der Meulen R : What Edge Computing Means for Infrastructure and Operations Leaders. Gartner; 2018."
}
|
[
{
"id": "186379",
"date": "13 Dec 2023",
"name": "Fahd Saghir",
"expertise": [
"Reviewer Expertise Industrial Time Series Analytics. Machine Learning for Time Series Data. Edge Analytics."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article describes a methodology for converting CSV files to JSON files. This paper has no added value to the research or industrial community. Moreover, there has been a dearth of papers in the recent past that have advised against the use of synthetic sensor data sets for training ML models.\nThe real concern to me is the statement, “The synthetic dataset performs slightly better than the original dataset”, which is a misleading statement, as the “synthetic” datasets do not present a real-world scenario.\nIn summary, the paper lacks depth and is stating the obvious in terms of IoT data processing. The paper also fails to address how such synthetic data can help train data for edge analytics use cases. A more obvious question to ask is why not use the actual sensor data on the edge to train ML models?\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-67
|
https://f1000research.com/articles/10-797/v1
|
12 Aug 21
|
{
"type": "Research Article",
"title": "Prevalence of substance abuse and its associated factors among medical students: a cross-sectional study",
"authors": [
"Mitesh Karn",
"Dipendra Kandel",
"Nuwadatta Subedi",
"Mitesh Karn",
"Dipendra Kandel"
],
"abstract": "Background: Substance abuse by medical students poses a significant risk not only on their personal life but also on their professional life by putting their patients at risk. Our study aims to find out the prevalence of substance abuse and factors associated with it among medical students. Methods: A descriptive, online-questionnaire based, cross-sectional study was carried out at Gandaki Medical College, a medical school in Gandaki Province of Nepal. Whole sampling technique was used. SPSS-25.0 software was used for statistical analysis. Descriptive statistics were used for analyzing demographic and substance abuse related variables. Chi square and Fishers exact test was used to find out if any differences existed in substance abuse by demographic characteristics. Results: Among 420 eligible participants, 219 participated in the survey (response rate: 52.2%). Alcohol was the most commonly used substance with overall lifetime prevalence of 58% followed by cigarette smoking and illegal drug abuse at 21.9% and 13.7%, respectively. The abuse of substances was significantly higher (p<0.05) in males, who were offered substances by friends, and amongst study participants who worked with an intoxicated colleague. The most common reason for substance abuse was “For pleasure, curiosity or to go along with friends” (23%, n=18). Major and minor dysfunction due to alcohol abuse was reported by 8(3.7%) and 33(15.1%) participants, while the same dysfunctions due to drug abuse were reported by 1(0.5%) and 14(6.4%) participants, respectively. Conclusions: The prevalence of substance abuse was high among medical students and was found to be associated with male gender, if offer of substances were made by friends, and amongst those who worked with an intoxicated colleague. This problem of substance abuse among medical students should be addressed timely as failing to do so might have serious consequences on the healthcare system of the country.",
"keywords": [
"medical students",
"substance-related disorders",
"alcohol abuse",
"smoking",
"drug abuse",
"consequences",
"health education",
"Nepal."
],
"content": "Introduction\n\nSubstance abuse refers to the harmful or hazardous use of psychoactive substances, including alcohol and illicit drugs and is one of the major problems globally.1 According to the Global Burden of Disease Study 2017, there were 585,000 deaths and 42 million years of “healthy” life lost as a result of the substance abuse.2 The World Drug Report 2019 estimated 271 million people, or 5.5% of the global population aged 15–64 years, had used drugs in the previous year, while 35 million people are estimated to be suffering from drug use disorders.3\n\nMedical students, the future healthcare professionals to be involved in the task of diagnosing and treating substance abuse are not immune to drug abuse, and the history of substance abuse within the medical fraternity is not new.4 Substance abuse by medical students poses risks and can also have serious consequences on their effectiveness and fitness to practice as good clinicians.5 Substance abuse by health care professionals can seriously influence their professional behavior, compromising the standard of delivered health care services and in turn, placing their patients at risk.6 It is believed that substance abuse among physicians starts early in their careers, and the importance of studying the lifestyles of medical students to detect substance abuse is well recognized.7 Researchers have suggested that substance abuse in medical school may be the root of the ongoing problem of increased substance abuse in practicing physicians.8–10\n\nData concerning substance abuse by medical students is scarce in Southeast Asia, especially from Nepal. To find out the prevalence of various types of substance abuse and factors associated with it, including consequences among Nepalese medical students, a cross-sectional study was carried out at a medical college in western Nepal.\n\n\nMethods\n\nA descriptive cross-sectional study was carried out among medical students (1st to 5th year) enrolled at Gandaki Medical College Teaching Hospital and Research Center (GMCTHRC), Nepal from 1st June 2020 to 1st July, 2020. Whole sampling technique was used. Data was collected from the study participants through a questionnaire sent via Google form which was sent to their email through class representatives of each year. Students who were not available through email contact or did not consent for their participation in the digital consent form were not included in the study. The participation was completely voluntary and no incentives were offered to the study participants. Anonymity was maintained throughout.\n\nStudy sample\n\nAll the medical students enrolled in the Bachelor of Medicine and Bachelor of Surgery (MBBS) program at GMCTHRC (n = 420) were included in the study. The study objectives and its implications were explained to the participants through the questionnaire sent via Google form on their email. The online method was preferred as physical classes had completely been cut down by the College administration in line with the COVID-19 protocols set up by the Government of Nepal.\n\nData was collected using a modified, online version of the Health Professional Questionnaire developed by Kenna and Wood.11 Permission was taken from Elsevier for using the questionnaire in our research. This tool was preferred as it had already been used successfully in a similar study among other healthcare students in Nepal.12 The final version of the survey did not require major changes and contained demographic information as well as the details and effects of substance abuse. We did not include the questions about university of study, faculty, course undertaken and religious beliefs that were originally present in the questionnaire.\n\nDemographic characteristics\n\nThe study participants were asked about their age, gender, year of study, place of stay and if there was a problem of alcohol and drug abuse in their family.\n\nSubstance abuse related characteristics\n\nWe asked the study participants about alcohol, cigarette and illegal as well as prescription drug use. The questions “how many times, if ever, have you smoked cigarettes?” and “recognize yourself as: Nondrinker/infrequent drinker/light drinker/moderate drinker/heavy drinker” were used, respectively, for lifetime cigarette smoking and alcohol use. The participants were asked about their lifetime experience and tendency of use of both prescription as well as illegal drugs, e.g. “how many times, if ever, have you smoked marijuana or hashish?” Participants were asked to rate the frequency of their use, varying from “0” times to “>30 times”. The prescription drugs under consideration were major opiates, minor opiates, stimulants, sedative-hypnotics, tranquilizers, anxiolytics and other prescription pain medicines. Illegal drugs included marijuana, cocaine and designer drugs such as ecstasy, LSD, Meth and Ketamine.\n\nThe study participants were also asked about how often they were offered alcohol and drugs by friends and how often they worked with colleagues who were intoxicated by such substances. We also asked about the reasons for substance abuse and the dysfunction it had on their daily life using a series of questions. The list of dysfunctions included 1) falling behind in work; (2) calling in sick or being late; (3) having trouble getting along with people; (4) worrying that you might be using too much or too often; (5) seriously considered suicide; (6) having an automobile accident or other type of accident; (7) seeing a psychiatrist, psychologist, or a counselor.12 The initial four effects were grouped as “minor dysfunction” and the remainder as “major dysfunction”. Subsequently, the minor and major dysfunction due to alcohol and drug abuse was calculated.\n\nThe data collected through Google forms were extracted to Microsoft Excel-13. Any response with missing data was excluded from the study. After data cleaning, it was imported and analyzed by using SPSS (Statistical Package for Social Sciences) 25. Demographic variables and substance abuse were analyzed using descriptive statistics. The frequency of use was recorded as 0 = never used and 1 = any use. Chi square test was used to examine any differences in substance abuse by demographic characteristics. Fisher’s exact test was applied for cell count less than 5. P value for statistical significance was set as less than 0.05.\n\nThis study was approved by the Institutional Review Committee of GMCTHRC (Ref no: 023/2076/2077). All the participants were informed about the study through the online form attached in the questionnaire sent to them and informed consent was obtained. Anonymity of the study participants was maintained throughout.\n\n\nResults\n\nTable 1 shows detailed demographic and general characteristics of study participants. Out of 420 medical students, 219 students participated in the study (response rate = 52.2%). There were considerably less participants from non-clinical years (n = 56, 35%) of medical school when compared to clinical years (n = 163, 63%). The mean age of study participants was 21.32 years, ranging from 18-30 years. Majority of respondents were females (n = 115, 52.5%) and most of them lived out of a rented property (n = 118, 53.9%).\n\nTable 2 shows the detailed prevalence of various substances abused by medical students. Alcohol was the most commonly abused substance with overall lifetime prevalence of 58% (n = 127), followed by cigarette smoking and illegal drug abuse at 21.9% (n = 48) and 13.7% (n = 30), respectively.\n\nWhen analyzing the distribution of substance use with various demographic variables, it was shown that the abuse of substances was significantly higher (p < 0.05) in males, if substances were offered by friends and amongst study participants who worked with an intoxicated colleague (Table 3).\n\n* Significant.\n\n# Fishers Exact test.\n\nOut of all the study participants, 78 respondents stated the reason for using substances. The most common reasons included: 1) for pleasure, curiosity or to go along with friends (n = 29, 37%); 2) supervising self for medical condition (n = 18, 23%); and 3) originally prescribed but now using on my own (n = 14, 18%). Table 4 shows the details regarding other reasons for substance abuse among the study participants.\n\nAs stated earlier, we grouped the harmful effects of substance abuse into “major” and “minor” dysfunction. Details of these dysfunctions due to alcohol and drug abuse have been presented in Table 5. Alcohol caused dysfunction in 41 respondents while drugs caused dysfunction in 15 respondents respectively.\n\nIn addition to all the other questions pertaining substance abuse, we also asked the study participants if they felt they used alcohol or drugs more than they would consider appropriate (Table 6). A total of 84% of the study participants (n = 184) responded that they didn’t feel they did, while 15.1% (n = 33) participants felt they used alcohol inappropriately. Only one participant each felt they used drugs and both substances inappropriately.\n\n\nDiscussion\n\nFrom our study, the prevalence of substance abuse was found to be 58% for alcohol, 21.9% for cigarette smoking and 13.7% for illegal drug use. Alcohol was the most commonly abused substance. Peer influence and sharing the workspace with an intoxicated colleague were significant predictors of substance abuse by medical students in our study. The most common reason for substance abuse was for pleasure, curiosity or to go along with friends. Our study participants also reported both major and minor dysfunctions due to substance abuse. The dysfunctions were higher among the alcohol using group and a majority of study participants admitted that they used alcohol inappropriately.\n\nThe overall prevalence of substance abuse among medical students varies from as low as 3% to as high as 84%.13 The prevalence varies widely between the geographic regions with higher rates in the more developed regions like Europe and North America. An extensive study carried out in medical students across the south-east Asian region reported the prevalence of smoking to be 31.7%.14 A multi-centric cross-sectional study carried out in India states the prevalence of substance abuse among medical students to be 31.5%.15 The precise prevalence of substance abuse is currently not known in Nepal for both the general population as well as the healthcare students. Among various single-institution studies in Nepal, the prevalence of substance abuse by medical students varies from 28% to about 64%.12,14,16–18 In a multi-centric study carried across three universities of Nepal, the overall prevalence of substance abuse among healthcare students was stated to be 42.8%12 but this study included only paramedical and allied science students. Nevertheless, comparison with available data showed that prevalence of substance abuse was higher in our study population.\n\nMedical students are the future doctors of the nation. That the high rate of substance abuse and its effects among medical students may significantly impair their learning ability and clinical judgement as physicians, affecting patient outcomes, cannot be denied. Further, substance abuse by medical students tarnishes the image that physicians have held for a long time as healers. Now is high time that this problem is seriously looked upon by stakeholders and policymakers for production of efficient and competent physicians both locally and globally.\n\n\nLimitations\n\nDue to the COVID-19 pandemic, the study was carried out through an online questionnaire. In a country where the internet penetration is only 57% and majority of students were stuck at home due to travel restrictions imposed by the Government of Nepal, this may have led to a decreased response rate in our study.19 Further, ours is a sensitive topic and there is a risk of response bias in our study. Another limitation is that our study is a single center study and the results from our study may not be generalizable across other parts of the country.\n\n\nConclusion\n\nThe prevalence of substance abuse was high among medical students and was found to be associated with male gender, if offer of substances were made by friends and amongst those who worked with an intoxicated colleague. Substance abuse by medical students may affect their professional career as independent physicians and significantly alter patient outcomes. Peer support programs and reward-punishment system may be effective interventions to curb this problem.\n\n\nData availability\n\nIn this study, participant-level data were collected. No data are available publicly because consent for publication of raw data was not obtained and the dataset could in theory pose a threat to confidentiality. Researchers interested in accessing the data will need to submit an official letter of request for the data to Gandaki Medical College Institutional Review Committee, 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\n\nReporting guidelines\n\nThis article was written in accordance with the STROBE guidelines.",
"appendix": "Acknowledgements\n\nWe would like to thank the students participating in the study. Dr Rajesh Gyawali from B.P. Koirala Institute of Health Sciences, Dharan is acknowledged for giving inputs to the manuscript.\n\n\nReferences\n\nWorld Health Organization: [Accessed 10th May 2020]. https://www.who.int/topics/substance_abuse/en/\n\nWorld Health Organization The Global Burden of Disease Study 2017: [Accessed 23rd April 2020]. Reference Source\n\nUnited Nations Office on Drugs and Crime World Drug Report 2019: [Accessed 23rd April 2020]. Reference Source\n\nAyala EE, Roseman D, Winseman JS, et al.: Prevalence, perceptions, and consequences of substance use in medical students. Med Educ Online. 2017; 22(1): 1392824. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMckay AJ, Hawthome VM, McCartney HN: Drug taking among medical students at Glasgow University. Br Med J. 1973; 1: 540–543. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAkvardar Y, Demiral Y, Ergor G, et al.: Substance use among medical students and physicians in a medical school in Turkey. Soc Psychiatry Psychiatr Epidemiol. 2004; 39: 502–506. PubMed Abstract | Publisher Full Text\n\nColeman EA, Honeycutt G, Ogden B, et al.: Assessing substance abuse among health care students and the efficacy of educational interventions. J Prof Nurs. 1997; 13: 28–37. PubMed Abstract | Publisher Full Text\n\nDumitrascu CI, Mannes PZ, Gamble LJ, et al.: Substance Use Among Physicians and Medical Students. Med Student Res J. 2014; 3(Winter): 26–35.\n\nMoore RD, Mead L, Pearson TA: Youthful precursors of alcohol abuse in physicians. Am J Med. 1990; 88(4): 333. PubMed Abstract | Publisher Full Text\n\nOreskovich MR, Shanafelt T, Dyrbye LN, et al.: The prevalence of substance use disorders in American physicians. Am J Addict. 2015; 24(1): 30–38. PubMed Abstract | Publisher Full Text\n\nKenna G, Wood MD: Prevalence of substance use by pharmacists and other health professionals. J Am Pharm Assoc. 2004; 44: 684–693. PubMed Abstract | Publisher Full Text\n\nPanthee B, Panthee S, Gyawali S, et al.: Prevalence and correlates of substance use among health care students in Nepal: a cross sectional study. BMC Public Health. 2017 Dec 12; 17(1): 950. Publisher Full Text\n\nRoncero C, Egido A, Rodríguez-Cintas L, et al.: Substance Use among Medical Students: A Literature Review 1988-2013. Actas Esp Psiquiatr . 2015; 43(3): 109–121. PubMed Abstract\n\nSreeramareddy CT, Suri S, Menezes RG, et al.: Self-reported tobacco smoking practices among medical students and their perceptions towards training about tobacco smoking in medical curricula: A cross-sectional, questionnaire survey in Malaysia, India, Pakistan, Nepal, and Bangladesh. Subst Abuse Treat Prev Policy. 2010; 5: 29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGoel N, Khandelwal V, Pandya K, et al.: Tobacco Use Among Undergraduate and Postgraduate Medical Students in India: A Multicentric Cross-sectional Study. Cent Asian J Glob Health. 2015 Feb 5; 4(1): 187.\n\nBudhathoki N, Shrestha MK, Acharya N, et al.: Substance Use Among Third year Medical Students of Nepal. J Nepal Health Res Counc. 2010 Apr; 8(16): 15–18. PubMed Abstract\n\nKhanal P, Ghimire RH, Gautam B, et al.: Substance use among medical students in Kathmandu valley. J Nepal Med Assoc. 2010; 49: 267–271. PubMed Abstract\n\nShyangwa PM, Joshi D, Lal R: Alcohol and other substance use/abuse among junior doctors and medical students in a teaching institute. J Nepal Med Assoc. 2007; 460: 126–129. PubMed Abstract\n\nGovernment of Nepal, Ministry of Communication and Information Technology: Digital Nepal’s network: unlocking Nepal’s growth potential.2018. [cited 2021 Mar 2]. Reference Source"
}
|
[
{
"id": "102054",
"date": "23 Dec 2021",
"name": "Prerna Bansal",
"expertise": [
"Reviewer Expertise Public health",
"preventive medicine",
"community medicine",
"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\nThe research title seems fine. The introduction can include the expected outcome of the research at the end. In methodology it is mentioned descriptive cross-sectional study design though some analytical tests like chi square and fishers exact test has been used. Kindly rectify. How the students were verified for identification via email is not mentioned. The result section is fine. In the discussion part the factors associated with substance abuse can be discussed more if literature available. Further scope of research and recommendations can be added at the end of discussion and conclusion. The limitations has been well addressed. The overall manuscript seems sound and clear. The problem has been highlighted well in the research. With minor revisions the manuscript can be accepted for indexing so that further scope of research can increase in the topic.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7653",
"date": "20 Jan 2022",
"name": "Mitesh Karn",
"role": "Author Response",
"response": "Thank you Dr. Bansal for taking out your time to review our manuscript. Based on your recommendations, we have added the expected outcome of the research in the last paragraph of the introduction section. We have rectified the design of the study as “cross sectional analytical”. Regarding how we verified emails of the study participants- we gave access to the google form to all the students enrolled in MBBS program in our system. Those students who logged in with their email in the google forms could fill the form. This way we indirectly verified their email but at the same time let them be anonymous by not collecting the emails of participants. Regarding the factors associated with substance abuse, studies exploring this aspect is scarce from Nepal. But we have added a short discussion about it from the available literature. We have also added further scope and recommendations."
}
]
}
] | 1
|
https://f1000research.com/articles/10-797
|
https://f1000research.com/articles/10-985/v1
|
29 Sep 21
|
{
"type": "Method Article",
"title": "Immersive virtual classroom as an education tool for color barrier-free presentations: a pilot study",
"authors": [
"Sayaka Fukuyama",
"Toki Saito",
"Daisuke Ichikawa",
"Ayako Kohyama",
"Hiroshi Oyama",
"Sayaka Fukuyama",
"Toki Saito",
"Daisuke Ichikawa",
"Ayako Kohyama"
],
"abstract": "Background: This study aimed to develop an experiential approach for understanding color vision variations using virtual reality technology. Methods: A virtual classroom was developed in a three-dimensional space, and 10 university students were tested to understand color vision variations. Results: Most participants noted that the virtual classroom was an excellent educational tool, which could help teachers understand the problems associated with [visual analog scale (VAS): mean ± standard deviation (SD), 9.55 ± 1.57] and obtain a better understanding of (VAS: mean ± SD, 9.04 ± 1.0) color vision variations. Conclusions: Our results show that this approach enhanced the participants' understanding of color vision variations; thus, it may assist children who suffer from this variation. It is necessary to evaluate the effectiveness of this approach for teachers.",
"keywords": [
"color vision variation",
"experiential education tool",
"virtual reality"
],
"content": "Introduction\n\nColor vision variations affect approximately 6–10% of males and 0.4–0.7% of females, although most of them live without experiencing significant problems.1 Such variations are classified into three grades: monochromatism, dichromatism, and trichromatism. They are also classified according to the disorder or lack of cone cells: protan deficiency, deutan deficiency, and tritan deficiency. It is difficult for patients with long or middle wave sensitive cones to distinguish red-green colors or for patients with short wave sensitive cones to distinguish blue-yellow colors. If two or more types of cone cells lack or have abnormal cones, it is classified as monochromatism; if the cone cells are normal, it is classified as normal trichromatism.2\n\nPatients with color vision variations often have problems in daily life, including school life, admission to schools, and obtaining a job. There is currently no effective treatment for this disorder. It is, therefore, necessary to consider how to use colors based on universal designs; this approach involves products or environments that are perceptible to patients with any color vision variations.3\n\nIn Japan, color vision tests during primary school medical examinations were abolished in 2002. However, before the termination of such tests, some studies showed that approximately 70% of primary or junior high school teachers were unaware of color vision variation. Approximately 80% knew that color vision variations could be detected during a medical examination using a color vision test. Moreover, approximately 90% of teachers were unfamiliar with the “Teaching Guidelines for Problems with Color Vision.” Thus, many teachers lacked knowledge and an understanding of color vision variations. After the termination of color vision tests, “Japanese Teaching Guidelines for Color Vision” was published to help teachers better understand color vision variation. In addition, the Color Universal Design Organization (CUDO) appraises and approves textbooks for the universal design of colors.4\n\nHowever, it can be difficult for teachers to become aware of students who have color vision variations, and most teachers have not used the publication “Japanese Teaching Guidelines for Color Vision.” Color vision variations can cause problems for students in three main areas: school life, admission to schools, and the ability to obtain a job.3 For example, students with color vision variations may be reprimanded by teachers who have limited knowledge of, or who are unable to detect, the disorder.\n\nIn 2014, the Ministry of Education, Culture, Sports, Science, and Technology in Japan instituted the “Partial Revision of Ordinance for Enforcement of School Health and Safety Act” for medical examinations to help teachers learn more about color vision variation and to better assist students with such a variation in learning and career guidance. However, this Act did not assist teachers in learning more about color vision variation.\n\nThere are some supporting tools for individuals with color vision variations that use color universal designs to assist them in recognizing colors.5,6 For example, designs have been developed so that affected individuals can perceive the colors in a design from a two-dimensional picture or on a website, but they are not designed to help educate teachers about color vision variations. Such designs involve a three-dimensional (3D) walking space without virtual reality (VR).7\n\nIt is well-known that virtual environments with a 3D space can assist in learning.8–10 However, few reports have applied this process to teaching the problems of students with color vision variations. This study aimed to develop an experimental learning approach for understanding color vision variations using a color vision variation simulator in a primary school classroom using VR technology.\n\n\nMethods\n\nVR was used to simulate and communicate the problems of students who have color vision variations. A primary school classroom and its teaching materials were constructed and projected in a VR space. Because approximately 70% of patients with a color vision variation are deutan deficient, this system simulated both deutan deficiency and normal trichromatism so that these two types of color vision could be compared.\n\nThe teaching materials constructed in the classroom were common to primary school classrooms; some were designed based on the publication “Japanese Teaching Guidelines for Color Vision,” which considers content about colors that are difficult for students with color vision variations to recognize or distinguish.\n\nPrevious studies used a head mount display (HMD) for experience-based simulation-enhanced learning,11–13 so in our system, an HMD was used for the VR experience. In addition, an analog stick was adapted as an operating device to enable users to operate and control their viewpoint manually and intuitively.\n\nAn iMac ME089J/A computer (Apple, Cupertino, CA) was used as hardware for the development of the execution environment, and Windows 7 Professional (Microsoft, Redmond, WA) was used as the operating system. Oculus Rift DK2 (Oculus VR, Irvine, CA) was used as the HMD for VR, and an Xbox360 controller for Windows (Microsoft) was used as an analog stick for controlling the viewpoint. Unity3D (Unity Technologies, San Francisco, CA), an integrated development environment, was used to construct the VR space with C# as the development language. “Japanese classroom set” (SbbUtutuya), a unity asset, was used as the 3D model for the virtual classroom and teaching materials. It is possible to develop this using an open-source software like Godot, but it is necessary to be certified by a professional organization that the software accurately displays color vision variations.\n\nBased on existing guidelines for color vision variations, seven parameters were chosen, designed, and constructed in the virtual classroom as contents that are difficult for students with color vision variations to recognize or distinguish: 1) the color of chalk, 2) the color of a calendar, 3) the color of flowers, 4) the colors of paints, 5) a red pen, 6) the colors of figures or graphs, and 7) the color coding used in maps (Figure 1).\n\n“Color vision variation Simulator for Unity” (Gulti, Tokyo, Japan), a unity asset, was used as a color vision simulator; it was developed based on the theory of color vision simulation by Brettel et al.,5,6 and was verified and approved by the CUDO.14 In this study, the “Deuteranope” mode was used to simulate a deutan deficiency. In addition, “dichromatism mode” and “trichromatism mode” were included; the former was applied to the “Simulate Intensity,” a parameter that showed the degree of simulation and was maximized, while the latter involved the state when the simulator was turned off.\n\nObjective\n\nThe test evaluated the usability and utility of the system for educational purposes.\n\nExperimental set-up and tasks\n\nThe participants, who did not have color vision variations, were recruited by snow-ball sampling. The test took approximately 30 min and was performed in the authors’ study room with a single participant and a test navigator. The participants were seated when using the system (Figure 2).\n\nBefore the test started, the objectives of the test were explained, and the participant completed the pretest questionnaire.18 Then, the participant received additional explanations regarding the outlines of the system and items in the virtual classroom that must be watched, and he/she was given instructions on how to operate the controller. The participant was then connected to the Oculus Rift to start the test. The Oculus Rift was set up based on the participant’s height.\n\nFirst, the participant experienced the dichromatism mode. During this experience, the navigator in charge asked seven questions about how the participant saw colors. The participant answered the questions orally while operating the viewpoint. Second, the participant experienced the trichromatism mode and answered the same questions. Finally, the participant completed a questionnaire about usability and utility (10 cm visual analog scale [VAS]) and finished the test.\n\nThere were four items in the questionnaire: ease of operation with the controller, immersion with the HMD, clearness of the display, and VR sickness. There were two questions about whether the participant learned about problems with color vision and whether the system promoted a better understanding of color vision variations.\n\nThe test was consistent with the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (Ministry of Education, Culture, Sports, Science, and Technology, Ministry of Health, Labor, and Welfare, 2014) and was performed after written informed consent was obtained from the participants. The questionnaire was completed anonymously and was self-administered. Personal information was treated in accordance with the Act on the Protection of Personal Information and information security policy of the University of Tokyo, Tokyo, Japan. Ethics approval was obtained from the Research Ethics Committee of the University of Tokyo (1139).\n\nR (R Development Core Team) was the statistical software used in this study. We calculated the average, standard deviation, and 95% confidence interval for the VAS scores after the participants’ experiences.\n\n\nResults\n\nThe participants were 10 university students (two males and eight females) at the Graduate School of Medicine; they were 21–47 years of age, with an average age of 26.6 years and a standard deviation (SD) of 7.3 years.18\n\nAll participants answered that they were familiar with the term “color vision variations,” but only four knew situations when students with color vision variations had difficulties. One participant answered that she had previously used a color vision variation simulation tool only to check the coloring of her website.\n\nTable 1 shows the results of the questionnaire regarding utility and usability.\n\nRegarding utility, whether they could learn the locations of color vision problems was 9.6 ± 0.6 (VAS average ± SD) and whether the system promoted a better understanding of color vision variation was 9.0 ± 1.0.\n\nRegarding usability, the ease of operation was 7.3 ± 1.7, immersion with HMD was 8.4 ± 1.6, clearness of the display was 5.8 ± 2.2, and VR sickness was 6.6 ± 2.5.\n\nSome remarks were included in the free description field, including “to use things which contents we have to understand only by color should be avoided,” “although the colors are similar, if the tints of them are different, some people could not tell them apart,” and “we should be careful of how to show graphs: how to use colors, designs or patterns.”\n\n\nDiscussion\n\nWe developed an experience-based educational support system using VR technology to provide information about color vision variations and evaluated its usability and utility for participants without color vision variations.\n\nApproximately 20% of the teachers in a previous report stated that they became aware of problems with the colors of chalk.14 The result of this study shows that a few participants had not noticed difficulties in students with a color vision variation, although they knew the term “color vision variations.” In addition, few participants had used color simulation tools. Although the participants were students, there was an apparent minimal interest in, or awareness of, the problems associated with color vision variations.\n\nIn the evaluation of the system’s utility, the average score was 9.6 for the question “How well do you understand what items are difficult for children with color vision variations to see or distinguish?” and the confidence interval was small. The other question item, whether the system promoted a better understanding of color vision variations, also received an average score of 9.0. This high evaluation is a result of the participants being presented with the world of the virtual classroom in both two-color and three-color modes, so that participants could experience the differences in color between the two modes alternately. Furthermore, for student participants with different color variations, only the problematic points as shown in Figure 1 were used, and the participants were operating the system while asking questions, which may have made it easier for them to focus on the target in the virtual classroom. It was suggested that additional educational effects could be achieved by organizing and expanding the content.\n\nThe usability evaluation results show that the average ease of operation with the controller was 7.3 (SD: 1.7). In this system, a video game controller was used as the operation device; therefore, whether the participants had experience operating a game controller influenced the results. In addition, because the movement speed of the viewpoint during rotation was set to slow to avoid VR sickness, the usability evaluation might have decreased.\n\nThe average immersion of the HMD was 8.4, suggesting that the participants received a high degree of immersion using the HMD because their actual surroundings were eliminated by wearing the HMD, and the display followed the motion of the participant’s head.\n\nRegarding the clearness of the display, the average (5.8) was lower than that for the other parameters, and the confidence interval varied widely. It is assumed that the experience of wearing the HMD differed among the participants. Color noise was sometimes seen in the display because the HMD tilted due to head movement or looseness of the headband. In addition, a participant stated that the HMD display resolution was low, which caused a decline in immersion. The HMD resolution should therefore be improved.\n\nMost participants experienced VR sickness. One participant experienced VR sickness during rotation movements with the controller. The VR sickness is consistent with many studies that reported that visual rotational motion could cause visually-induced motion sickness.15–17 An unfamiliar controller operation might have caused VR sickness. The user interface should therefore be improved, and the ability to rotate the controller should be restricted.\n\nFrom the results of the free-response question regarding whether one’s understanding of color vision variations increased, the reason for the better understanding of the changes in color vision was not only that the participants answered the questions while comparing the three-color vision modes with the two-color vision modes, but also that the navigator explained to the participants the specific things to think about during the experience. The system could be used to develop better graphs for PowerPoint presentations, not just by schoolteachers and staff but also by students and other occupational workers.\n\nThere are limitations to this study. First, the participants were students even though the system was developed for teachers. Second, the evaluations were subjective, and the teaching efficacy could not be measured quantitatively.\n\n\nConclusions\n\nWe have developed a VR system that allows children with color vision mutations to experience their color vision and demonstrate its properties. With this system, teachers will be able to increase their knowledge of color vision mutations and solve color vision problems in the classroom. In the future, it is necessary to evaluate the effectiveness of this approach for teachers.\n\n\nData availability\n\nOSF: Immersive virtual classroom as an education tool for color barrier-free presentations: A pilot study data. https://doi.org/10.17605/OSF.IO/3KJVR.18\n\nThis project contains the following underlying data:\n\n• manuscript72900RawData.xlsx (raw 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\nOSF: Immersive virtual classroom as an education tool for color barrier-free presentations: A pilot study data. https://doi.org/10.17605/OSF.IO/3KJVR.18\n\nThis project contains the following extended data:\n\n• manuscript72900_Extended_data.pdf (blank copy of the questionnaire)\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 authors are grateful to Drs. T. Sakamoto and S. Ino for useful discussions. We also thank the students at the University of Tokyo who participated in the evaluation.\n\n\nReferences\n\nBirch J: Diagnosis of defective colour vision. Elsevier Health Sciences; 2001.\n\nKeene DR: A Review of Color Blindness for Microscopists: Guidelines and Tools for Accommodating and Coping with Color vision variation. Microsc. Microanal. 2015; 21(2): 279–289. PubMed Abstract | Publisher Full Text\n\nCole BL: The Handicap of Abnormal Colour Vision. Aust. J. Optom. 1972; 55(8): 304–310. PubMed Abstract | Publisher Full Text\n\nOkabe M, Ito K: Color Universal Design (CUD)-How to make figures and presentations that are friendly to Colorblind people. J* Fly Data Depos. Drosoph. Res. 2008.\n\nViénot F, Brettel H, Ott L, et al.: What do colour-blind people see? Nature. 1995; 376(6536): 127–128. PubMed Abstract | Publisher Full Text\n\nBrettel H, Viénot F, Mollon JD: Computerized simulation of color appearance for dichromats. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 1997; 14(10): 2647–2655. Publisher Full Text\n\nKubota S, Seki H, Kano T, et al.: Development and Application of Color Universal Design Support System for Pedestrian Space. IPSJ J. 2011; 52(1): 140–152. Publisher Full Text\n\nMills S, De Araújo MMT: Learning through virtual reality: a preliminary investigation. Interact. Comput. 1999; 11: 453–462. Publisher Full Text\n\nPanagiotis KK, Konstaninos G, Stylianos M, et al.: E-Learning through virtual reality applications: The case of career counseling. Int. J. Technol. Learn. 2014; 21(1): 57–68. Publisher Full Text\n\nShen C, Ho J, Kuo T-C, et al.: Behavioral Intention of Using Virtual Reality in Learning. Proceedings of the 26th International Conference on World Wide Web Companion. International World Wide Web Conferences Steering Committee; 2017, pp. 129–137.\n\nFreina L, Ott M: A literature review on immersive virtual reality in education: State of the art and perspectives. Proc. eLearning Softw. Educ. (eLSE) (Bucharest, Rom. April 23–24, 2015) 2015.\n\nMoro C, Štromberga Z, Raikos A, et al.: The effectiveness of virtual and augmented reality in health sciences and medical anatomy. Anat. Sci. Educ. 2017; 10: 549–559. PubMed Abstract | Publisher Full Text\n\nPeden RG, Mercer R, Tatham AJ: The use of head-mounted display eyeglasses for teaching surgical skills: A prospective randomised study. Int. J. Surg. 2016; 34: 169–173. PubMed Abstract | Publisher Full Text\n\nCUDO: Color Universal Design Organization. [Accessed: 31-Aug-2017]. Reference Source\n\nGolding JF, Gresty MA: Motion sickness. Curr. Opin. Neurol. 2005; 18: 29–34. PubMed Abstract | Publisher Full Text\n\nGolding JF: Motion sickness susceptibility. Auton. Neurosci. Basic Clin. 2006; 129(1–2): 67–76. PubMed Abstract | Publisher Full Text\n\nPalmisano S, Mursic R, Kim J: Vection and cybersickness generated by head-and-display motion in the Oculus Rift. Displays . 2017; 46: 1–8. Publisher Full Text\n\nOyama H: Immersive Virtual Classroom as an Education Tool for Color Barrier-Free Presentations: A Pilot Study Data. OSF . September 15. 2021. Publisher Full Text"
}
|
[
{
"id": "98213",
"date": "03 Nov 2021",
"name": "Alice Skelton",
"expertise": [
"Reviewer Expertise Colour vision",
"cognitive development"
],
"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 method suggested is using a VR classroom setting and applying the built in filters for modelling different types of colour vision deficiency (CVD) so that people without CVD can better understand the perceptual experience of people with CVD. 10 participants wear the VR headset and view a classroom environment under different examples of CVD before being asked to self-report if they have learnt about what people with CVD experience & if they think it’s useful. They are also asked some basic questions about the usability of the set up. The majority of participants do report learning about CVD. It appears that showing people what colour vision deficiency might be like makes the majority of participants understand a bit better about what colour vision deficiency is like.\nThere are a lot of inaccuracies in the introduction in defining what variations in colour vision are: e.g. a reference to 'trichromatism' as being a colour vision variation affecting 6-10% of males, trichromacy is actually typical colour vision; \"It is difficult for patients with long or middle wave sensitive cones to distinguish red-green colors\" is also incorrect - having L and M cones means you are able to discriminate reds and greens. Many textbooks with a section on colour vision would be a better place to start to find out about the physiology of colour vision (e.g. a nice accessible version is: Snowden et al. 20121).\nThe method of demonstrating the perceptual experience of people with colour vision deficiencies (CVD) in order to help teachers and educators better understand the experience of children in their classrooms is a good idea. It is a little hard to see what this particular method offers over what can already be gained from CVD simulators however, and this method is not compared to any other method of educating people on the experience of living with CVD, so it's hard to know how effective it is in comparison to these other methods which would likely be more accessible in terms of equipment for the majority of educators.\n\nIt’s important that interventions to teach people about individual differences are teaching people accurate information. The paper does not report how accurate the simulated versions of the classrooms are in matching the perceptual experience of people with CVD. There has been rigorous testing of the accuracy of simulations (e.g. Lillo et al. 20142) which shows there is some variation in how accurate these simulations are.\nMost CVD simulators do not use calibrated displays which can most accurately capture the perceptual experience of a student with CVD, and that technical aspect is also missing from the current method.\n\nIs the rationale for developing the new method (or application) clearly explained? No\n\nIs the description of the method technically sound? Partly\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? No",
"responses": [
{
"c_id": "7399",
"date": "20 Jan 2022",
"name": "Hiroshi Oyama",
"role": "Author Response",
"response": "Dear Dr. Alice Skelton, We thank you for careful reading our manuscript and for giving useful comments. This research aims to propose a methodology on CVD using a simulation tool based on VR technology rather than a comparative study with existing color simulations. It is based on Situated Learning Theory to support education about CVD using VR technology. >There are a lot of inaccuracies in the Introduction.... -> We will check our references and revise the first paragraph of the Introduction. >The method of demonstrating the perceptual experience of people with colour vision .... ->The reason for choosing medical students as subjects were to reduce knowledge bias about CVD in the evaluation. >It’s important that interventions to teach people about individual differences.... ->The \"Color vision variation Simulator for Unity\" used in this project is a simulation tool certified by CUDO (Color Universal Design Organization: https://www2.cudo.jp/ wp/). The HMD resolution is 1,920 x 1,080, which enables full high definition-like display. However, following your suggestion, we will add \"The Simulcheck method will be needed to be evaluated.\" in the limitation paragraph. Sincerely,"
}
]
},
{
"id": "99517",
"date": "10 Nov 2021",
"name": "Teresa M Chan",
"expertise": [
"Reviewer Expertise Medical education",
"Health professions education",
"Digital learning"
],
"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 inviting me to complete this peer review. Overall I see the merit in this paper and feel that it is worthy of indexing.\nMy suggested edits are to help you shift this article from a surface reporting of what you did towards a more scholarly report of the techniques used.\nMajor concerns:\nWhy did you chose a visual analogue scale for this study? There is very little in the literature around the selection of this particular VAS scale for the purposes of your study. More substantiation (and/or more details about pilot testing) of your measurement tool would be imperative prior to indexing. What is the interrater or intrarater reliability of the VAS?\n\nI am perplexed about the study design - there seems to be only 1 arm of individuals. The layout of the introduction led me to believe you might compare groups of individuals with colour vision variations to those who are not.\n\nPlease add your sample size calculation for this study. It is unclear why you are even reporting standard deviations or 95% CI since there is no comparator group. Please more thoroughly discuss this in the Data Analysis section as currently they do not appear beyond the table. I would suggest it is important to highlight these in the text and also discuss them in your discussion.\n\nFinally, your utility and usability framework are unclear to me. What prior literature informed your survey tool? Please cite supporting references that helped you design your study.\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? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "7437",
"date": "20 Jan 2022",
"name": "Hiroshi Oyama",
"role": "Author Response",
"response": "Dear Dr. Teresa M. Chan, We thank you for your fruitful suggestions, especially for suggesting a better study design and valuable comments. (1) Why did you choose a visual analog scale for this study? Res) Although there have been reports of VAS being used in usability evaluations of surgical VR systems, there have been no reports of evaluation scales measuring the impact of VR systems such as this one. We also considered using the Likert scale but did not use it because it has the disadvantage that different respondents give different reasons for their choices. The VAS is a scale that allows respondents to freely answer their rating results in a continuous band, the length of which is on a line. It is vital to motivate respondents to answer honestly. Therefore, motivating respondents to answer is a significant advantage of the VAS method, so we used it this time. In addition, the VAS method has the advantage of measuring minute differences in respondents' impressions and being able to relativize and quantify information that is difficult to relativize and quantify. Therefore, we believe that the VAS method can accurately measure users' perceptions of the VR system. As you suggested, it is necessary to evaluate the validity of this scale. We will add the verification of the validity of this scale in the limitation section of this study. Ref) Jokinen, E., Mikkola, T. S., & Härkki, P. (2020). Simulator training and residents' first laparoscopic hysterectomy: a randomized controlled trial. Surgical endoscopy, 34(11), 4874-4882. DOI: 10.1007/s00464-019-07270-3 (2) I am perplexed about the study design - there seems to be only one arm of individuals. Res) This VR system is intended to be an educational tool to assist teachers in making appropriate responses to children with color vision variations. As such, this study corresponds to Phase I of the clinical trial. As you suggested, the efficacy study (Phase II) will be conducted on new teachers in elementary and middle schools. (3) Please add your sample size calculation for this study. … Res) This study is a Phase I clinical trial in advancing the clinical application of VR systems. The incidence of adverse events in VR systems has ranged from 30% (Chen et al., 2011) to over 80 % (Kim et al., 2005). The median value of the VAS scale is 5. If it was a normal distribution, the sample size was calculated using a two-tailed t-test of the mean values of one group with a significance level of α = 5% and a power of 80% with a mean difference of 1.5 and a standard deviation of 1. The calculation resulted in a sample size of 8.06. Since this is a Phase I study, standard deviations and confidence intervals are shown to determine the characteristics of the population. We will add this information to the data analysis and discussion as you suggested. We think that a sample size of 30 or more is appropriate. We will add the sample size to the limit. Ref) Chen, W., Chen, J. Z., & So, R. H. Y. (2011). Visually induced motion sickness: Effects of translational visual motion along different axes. Contemporary ergonomics and human factors, 2011, 281-287. Kim YY, Kim HJ, Kim EN, Ko HD, Kim HT (2005) Characteristic Changes in the Physiological Components of Cybersickness. Psychophysiology 42(5):616–662. DOI: 10.1111/j.1469-8986.2005.00349.x Rebenitsch, L., & Owen, C. (2016). Review on cybersickness in applications and visual displays. Virtual Reality, 20(2), 101-125. DOI: 10.1007/s10055-016-0285-9 (4) Finally, your utility and usability framework are unclear to me. …. Res) The evaluation framework and survey tools for this study were based on the following paper. We will add the following study in the Method section as a reference. Pallavicini, F., Pepe, A., & Minissi, M. E. (2019). Gaming in virtual reality: What changes in terms of usability, emotional response and sense of presence compared to non-immersive video games? Simulation & Gaming, 50(2), 136-159. DOI: 10.1177/1046878119831420"
}
]
},
{
"id": "98822",
"date": "01 Dec 2021",
"name": "Juan Luis Higuera-Trujillo",
"expertise": [
"Reviewer Expertise Virtual reality",
"neuroarchitecture"
],
"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 contains the seeds of an interesting and very socially useful approach. In that sense, I should congratulate the authors. However, it has the major problem of presenting a very low sample size and, more critically, not fully aligning the objective with the methods employed. I understand that it is a pilot study. But a \"pilot study\" is not a concept that legitimises lack of depth in the paper. Such studies should try to express the methodology as justifiably and clearly as possible. However, the article (in its current version) fails to express this adequately. Other limitations of the article are a weak introduction, and discussion section. In the following review, I try to give my view on how the authors could improve the article.\nIntroduction\nThe introduction is easy to follow and well structured. However, it contains the following weaknesses:\nThe first paragraph is illustrative. But it would require further explanation, as it introduces concepts such as \"dichromatism\" with which readers may not be familiar.\n\nA scholarly introduction should state the problem and put it in context with related literature. In this introduction the problem is stated, but it lacks academic rigour. It is a relatively short introduction, citing only 10 references. It reads more like a professional report than an academic introduction. I suggest the authors improve the scientific scope of this text.\n\nMethods\nThe comment about \"Godot\" doesn't really make sense. If it was not used, it should not appear.\n\nThe choice of the seven parameters (the colour of chalk, etc.) should be justified.\n\nThe general experimental methodology is explained textually, but it would be a significant support to elaborate a figure indicating the whole process. The aim of this section is to allow the replicability of the study; and in its current version this would not be possible.\n\nThe questionnaires used by the authors should be listed in a table in this section. It is not enough to present the questions together with the results in the results section. The methods section should be self-explanatory.\n\nI understand that the questionnaires used are partly based on other questionnaires. They should be referenced.\n\nThe description of the sample should not be included in the results section, but in the methods section. On the other hand, the following aspects of the sample are critical: (1) very low number of participants; (2) very different ages, especially considering the low number of participants; and (3) unbalanced gender.\n\nResults\nQuestion 4 of the usability questionnaire could be confusing: do high scores refer to a high degree of sickness? I understand that it meant the opposite, and that the VAS corrects this problem. But for future studies I would recommend to the authors that, if they develop their own questionnaires, all questions should be equally oriented. For example, in this question, it would have been better: \"4) The degree to which you are free of VR sickness\", or something similar.\n\nIt is confusing how it can be said \"We have developed a VR system that allows children with colour vision mutations to experience their colour vision and demonstrate its properties\", when the whole sequence has been aimed at testing the tool with university students without such problems.\n\nDiscussion\nAn academic discussion tries to put the results in context with the available literature. However, in this case it is essentially limited to explaining the results. The commentary on the results should be in the Results section, not in the Discussion one. The discussion should attempt to contextualise them. This does not occur in the current version of the study (or it occurs very briefly: only in the last and antepenultimate paragraphs of the discussion). I encourage authors to improve this section in order to follow the structure of a strong research article.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? No\n\nAre sufficient details provided to allow replication of the method development and its use by others? No\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": "7536",
"date": "20 Jan 2022",
"name": "Hiroshi Oyama",
"role": "Author Response",
"response": "Dear Dr. Juan Luis Higuera-Trujillo, We thank you for carefully reading our manuscript and for giving valuable comments. The ultimate goal of this research is to propose a first-person experiential education method using VR to help participants (especially new teachers) respond appropriately to children with color vision variations at the school. This paper is a report on the first stage of realizing this goal. It is positioned as a Phase 1 study of a clinical trial. Therefore, we mainly examined whether there would be any problems for healthy people and whether there would be any usability problems during the experience. The next step will be to examine the impact on new teachers. We will revise the manuscript based on your feedback. Sincerely Hiroshi"
}
]
}
] | 1
|
https://f1000research.com/articles/10-985
|
https://f1000research.com/articles/9-1361/v1
|
23 Nov 20
|
{
"type": "Research Article",
"title": "Narcolepsy in Parkinson's disease with insulin resistance",
"authors": [
"Alisha Chunduri",
"Wim E. Crusio",
"Anna Delprato",
"Alisha Chunduri",
"Wim E. Crusio"
],
"abstract": "Background: Parkinson’s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions: We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.",
"keywords": [
"Parkinson’s disease",
"narcolepsy",
"insulin resistance",
"diabetes",
"circadian"
],
"content": "Introduction\n\nParkinson’s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance1. The motor difficulties associated with PD are attributed to the loss of dopaminergic neurons in the substantia nigra1. There are also non-dopamine lesions that are involved in PD that include the caudal group of intralaminar nuclei (located in dorsal thalamus), and subcoeruleus nuclei1. The main genetic cause of PD is attributed to mutation of the LRRK2 (leucine-rich repeat kinase 2) gene2,3.\n\nSleep disruption is another manifestation of LRRK2-PD and is often more disturbing than the motor symptoms4. Most PD patients have daytime sleep attacks and REM sleep disorder that resemble narcolepsy associated sleep symptoms such as excessive daytime drowsiness, sleep paralysis, hallucinations5, and in some cases episodes of cataplexy6. People with narcolepsy frequently enter REM sleep rapidly, within 15 minutes of falling asleep and the muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep7. Alleles of the HLA-DQB1 (major histocompatibility complex, class II, DQ beta 1) gene are associated with a predisposition to narcolepsy8, PD9, and Type I diabetes10. There is also a significantly increased risk of PD among patients with a history of diabetes11.\n\nBesides HLA-DQB1, the relationship between PD, narcolepsy, and IR may be in part attributed to the hypocretins/orexins which are produced by the HCRT gene12. Hypocretins are neurotransmitters that are manufactured by a small number of neurons in the hypothalamus13. They act to stimulate target neurons and promote wakefulness while suppressing rapid-eye-movement (REM) sleep14. Research has shown that there is a massive loss of hypocretin neurons in patients of both PD and narcolepsy and it is hypothesized that the reduction of hypocretin may be the underlying pathogenesis of the narcoleptic symptoms in PD5,15,16. In addition to their role in narcolepsy and PD, hypocretins modulate glucose and insulin metabolism15. In this study we explore the connection between PD, narcolepsy, and IR using an integrative genomics and systems biology approach.\n\n\nMethods\n\nMicroarray data was collected from the Allen Brain Database using the Human Brain Atlas. To obtain the data, a gene search for LRRK2, HLA-DQB1, and HCRT was performed. Each of these genes were used to query the atlas for correlates to the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus using the dropdown menu for each of the six donor post-mortem brains available in the Allen Human Brain Atlas.\n\nGenes whose expression pattern correlated with LRRK2, HLA-DQB1, and HCRT were collected for analysis. Correlates with a range of Pearson r values from 0.6 to 1.0 were considered in the analysis (Extended data, Workbook 117). The rationale was to investigate genes with a similar expression pattern in order to identify gene correlates specific and common to LRRK2, HLA-DQB1, and HCRT. Risk factor genes and genes contributing to PD, narcolepsy, and IR were obtained from OMIM, Harmonizome, and GeneWeaver.\n\nEach geneset was evaluated using Gene Ontology (GO) enrichment for clustering, pathways, and keywords using the Database for Annotation, Visualization and Integrated Discovery (DAVID, version 6.8) and the Gene Ontology databases with integrated tools for analysis. Clustering was done in DAVID using the default parameters which include medium stringency settings and a kappa similarity value of 3. The Benjamini corrected P-value was used to determine enrichment significance. The pathway enrichment was performed using KEGG and Panther pathways. The pathways were analyzed manually and evaluated based on shared themes. For the keyword enrichment, a keyword search of the DAVID functional annotation table output was used to identify genes associated with relevant traits related to LRRK2, HLA-DQB1, and HCRT function. The keywords considered were ‘sleep’, ‘circadian’, ‘parkinson’, ‘locomotion’, ‘dopamine’, ‘behavior’, ‘learning’, ‘memory’, and ‘transcription factor’. Geneset overlap was assessed using Venny 2.0, an online program that compares lists of items to determine the common and unique genes between LRRK2, HLA-DQB1, and HCRT within and among each brain region (hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus). Geneset overlap was visualized with the UpSet Library in RStudio, R Version 4.0.2.\n\nThe String database (version 11.0) was used to build a protein-protein interaction network (PPI) for LRRK2, HLA-DQB1, HCRT and CAMK1D which was identified in this study as the only common risk factor gene associated with PD, narcolepsy and IR (Results section: \"Functional analysis of PD, narcolepsy and IR risk factor and related genes\"). The network was constructed based on experimentally validated interactions using the medium confidence score of 0.4. The combined scores for the interactions are computed by combining the probabilities from the different evidence channels and corrected for the probability of randomly observing an interaction. First and 2nd shell interactions are included in the network. The network was exported from STRING and analyzed in Cytoscape (version 3.7). Network bottlenecks and clusters were identified with Cytoscape plugins CytoHubba (version 0.1) and MCODE (version 1.6.1), respectively. ClueGo (version 2.5.7) was used to analyze the common risk factors and contributing genes for PD, narcolepsy, and IR. The nodes in the network have been manually arranged for proper visibility. Select enriched terms are included in the network (Figure 3A). All of the enriched terms are provided in Extended data, Workbook 5, sheet 518.\n\n\nResults\n\nThe cluster analysis for the LRRK2, HLA-DQB1, and HCRT gene correlates for each brain region resulted in significant enrichment categories for only HLA-DQB1 related genesets. For LRRK2 and HCRT there are several instances in which clusters contained enrichment terms for insulin, diabetes, PD, other neurodegenerative disorders, and circadian processes but these did not achieve significance based on the corrected P value criteria. Also, of note for almost every set of correlates, there were many significant enrichment categories and corresponding genes associated with keratinocytes/keratin and olfaction. The clustering results for each set of gene correlates are listed in Extended data, Workbook 219.\n\nFor the HLA-DQB1 clusters, the significant enrichment terms are: dorsal thalamus: hsa05012:Parkinson's disease (P=4.38E-06), 31 genes and hsa04940:Type I diabetes mellitus (P=0.03), 10 genes; subcoeruleus nucleus: hsa04940:Type I diabetes mellitus (P=6.13E-05), 15 genes, and pons: hsa04940:Type I diabetes mellitus, six genes (P=0.001). The other genes and enrichment categories clustering with PD in the dorsal thalamus are related to mitochondria processes such as oxidative phosphorylation and electron transport as well as Alzheimer’s disease (AD) and Huntington disease (HD).\n\nAmong the sets of gene correlates for LRRK2, HLA-DQB1 and HCRT, there are 10 common genes in both the dorsal thalamus and subcoeruleus nucleus (HNRNPU, GDF11, ROCK1, GABRA4, PFKFB2, ZNF846, PAK2, A_32_P232747, SLC9A3R2, and DISC1; Figure 1B). Among the relevant genes are ROCK1, which is involved in negative regulation of neuron apoptotic processes, DISC1 associated with neuron migration, and HNRNPU involved in circadian regulation of gene expression. The ten common genes in the subcoeruleus nucleus are LAMP2, LOC653110, HNRNPU, SLC6A6, PHTF2, ITGB2, OPA3, GLYAT, HCN4, and HMGB1, among which the relevant ones to this study are HNRNPU, which as mentioned above is involved in circadian regulation of gene expression and insulin signaling, ITGB2, which is associated with PD and IR, and HMGB1, which is a ligand for the RAGE receptor. Among the sets of gene correlates for LRRK2, HLA-DQB1, and HCRT, there are no common correlated genes in the hypothalamus and pons.\n\nShared correlates for LRRK2, HLA-DQB1 and HCRT over all brain regions. X-axis, Intersection size; Y-axis, Gene number and brain regions.\n\nA detailed description of all shared genes and their associated function for each brain region is provided in Extended data, Workbook 3 (sheets 1–8)20. Briefly, the dorsal thalamus and subcoeruleus nucleus have the largest number of shared correlates between LRRK2, HCRT, and HLA-DQB1. Many of these genes for both brain regions are associated with neuron, insulin, and dopamine related processes. There are also several genes connected directly to PD. In sharp contrast, however, the dorsal thalamus associated correlates have many genes linked to circadian function.\n\nIn the dorsal thalamus, the relevant genes are associated with neuron function (negative regulation of neuron apoptotic process, neuron projection development and regulation, neuron differentiation, neuron fate commitment, neuron death in response to oxidative stress, neuron regeneration), circadian processes (regulation of circadian rhythm, circadian entrainment, circadian regulation of gene expression, regulation of circadian rhythm, entrainment of circadian clock by photoperiod), and insulin signaling (insulin secretion, insulin receptor signaling, insulin secretion). Other genes of interest are related to dopamine (dopaminergic neuron differentiation, regulation of dopamine uptake involved in synaptic transmission, positive regulation of dopamine secretion, Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation, dopamine receptor binding, dopamine biosynthetic process, adenylate cyclase-activating dopamine receptor signaling pathway) and also behavior (locomotory, feeding, learning, memory and vocalization, response to stimulants).\n\nIn the subcoeruleus nucleus, the relevant genes are also associated with neuron function (negative regulation of neuron differentiation, dopaminergic neuron differentiation, neuron apoptotic process, negative regulation of neuron differentiation, forebrain neuron differentiation), insulin signaling (insulin secretion, insulin receptor signaling pathway, negative regulation of insulin receptor signaling pathway, positive regulation of insulin secretion, diabetes mellitus), dopamine related processes (dopaminergic synapse, dopamine biosynthetic process, dopaminergic neuron differentiation, regulation of synaptic transmission, dopaminergic dopamine biosynthetic process from tyrosine), and behavior (locomotory, vocal learning, response to fear, grooming, response to stimulants).\n\nThere are few shared correlated genes in the hypothalamus and pons. For the hypothalamus, the most pertinent genes are involved in neuron migration and circadian processes. In the pons, the relevant genes are concerned with negative regulation of neuron apoptotic processes, neuron projection, circadian regulation of gene expression, and hippocampus and pyramidal neuron development.\n\nGeneset overlap of the correlates for LRRK2, HLA-DQB1, and HCRT was assessed within each brain region (see Extended data, Workbook 3, sheets 9–1120). Of the LRRK2 correlates,1.6% were common in all 4 brain regions. Among these are genes associated with insulin (MAX, NUCKS1, PIK3R1, PTPN11), diabetes (PIK3R1) and circadian-related processes (HNRNPU, BHLHE41). Several transcription factors were also present (MAX, SKI, ATF7IP, NUCKS1, BHLHE41, NR2C2, PIK3R1). One of these, BHLHE41, acts as a negative regulator of orexin, controls circadian rhythms, and is associated with short sleep syndrome and advanced sleep phase disorder. For HLA-DQB1, 1.2% of the correlates are common in all brain regions; relevant associated themes include PD and dopamine (SLC18A1) insulin (HLA-DRB5, HLA-DOA, HLA-DQA1, HLA-DQB1) and transcription factors (PYCARD, SOX8, FOXE3, LGALS9, HMGB1, ZNF446). Only 0.2% of the HCRT correlates are common among all brain regions considered. This includes HCRT itself and an insulin associated gene, GHSR. Of note, the MOG gene, which is present among the HLA-DQB1 correlates of the subcoeruleus nucleus and HCRT correlates of the hypothalamus, is a risk factor for narcolepsy and is linked to PD.\n\nFrom the GO analysis of the gene correlates, a functional annotation table was generated for GO Biological Process. Genes associated with keywords were obtained and their frequencies determined. The keyword categories used are as follows: sleep, circadian, Parkinson, locomotion, dopamine, insulin, behavior, learning, memory, and transcription factor (Figure 2A–C and Extended data, Workbook 4, sheets 1–621). Each of the correlates for the genesets are evaluated for keywords related to the phenotypes of narcolepsy, PD, and IR in the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Most of the keywords of the three sets of gene correlates are associated with subcoeruleus nucleus.\n\nRepresentative keyword enrichment of the gene correlates of LRRK2, HLA-DQB1 and HCRT in the Hypothalamus, Dorsal Thalamus, Pons and Nucleus Subcoeruleus based on GO term classification. (A) LRRK2 gene correlates (B) HLA-DQB1 gene correlates (C) HCRT gene correlates. X-axis, keyword categories; Y-axis, frequency of occurrence.\n\nThe LRRK2 gene correlates have the highest frequency of the keyword categories. The highest represented categories are: transcription factor (hypothalamus), insulin, behavior, learning, memory, locomotion (dorsal thalamus), dopamine, Parkinson, and sleep (subcoeruleus nucleus) and circadian processes (equal frequency in dorsal thalamus and subcoeruleus nucleus).\n\nThe highest represented keyword categories for HLA-DQB1 are behavior, insulin, transcription factor, circadian, memory, dopamine, sleep (subcoeruleus nucleus), locomotion (hypothalamus), and learning (equal frequencies in the hypothalamus and subcoeruleus nucleus). The highest represented categories of HCRT are transcription factor, behavior, insulin, circadian, dopamine, Parkinson, memory, sleep, locomotion (subcoeruleus nucleus), and learning (hypothalamus).\n\nPD, narcolepsy, and IR risk factor and related genesets were evaluated to identify a common set of genes associated with the three disorders (Extended data, Workbook 5, sheets 1–418). There were 38 shared genes between the PD and narcolepsy genesets. CAMK1D is the only gene common among the three genesets for PD, narcolepsy, and IR and it is a Calcium/Calmodulin kinase that is upregulated in PD patients and is also a risk factor for Type 2 diabetes22,23.\n\nOf the common PD and narcolepsy genes, several were directly associated with PD and narcolepsy behavioral phenotypes such as locomotion (DRD2, DRD3, DRD4, GDNF, SLC18A2), sleep (HTR2A, DRD2, DRD3, GRIN2A, NLGN1), circadian processes (PPARGC1A, CACNA1C, DRD2, DRD3, DRD4, GRIN2, MAPK1, NLGN1), circadian entrainment (CACNA1C, GRIN2A, MAPK1), learning (COMT, DRD1, DRD2, DRD3 GRIN2A) and memory (GRIN2A, HTR2A, COMT, DRD1, DRD2, DRD3). There were two common genes between the PD and IR genesets: RREB1, which is a transcription factor, and ANKFY1, which is involved in vesicle trafficking and is also implicated in Type 2 diabetes. There is one common gene between narcolepsy and IR: HLA-DQB1, which is the narcolepsy associated gene under study here.\n\nThe enrichment results are visualized as a network of functionally grouped terms and pathways and listed in the accompanying bar graph (Figure 3A, B, Extended data, Workbook 5, sheet 518). The most significant term of a given group is highlighted as the leading term in the network which is indicated by color. The most significant terms emphasized in the graph are dopaminergic synapse (ten genes, KEGG ID:04728, P=2.77E-09) and the AGE-RAGE signaling pathway in diabetic complications (seven genes, KEGG ID:04933, P=4.70E-06) both of which are relevant to PD and IR. Other relevant enriched GO Terms include Type I diabetes mellitus (four genes, KEGG:04940, P=6.27E-04), Type II diabetes mellitus (four genes, KEGG:04930, P=7.54E-04), and Amyotrophic lateral sclerosis (five genes, KEGG:05014, P=9.56E-05). The other enriched terms in the network also represent pathways linked to the reward system, serotonin signaling, immune system function, and insulin regulation. There are several points of convergence in the graph where the enriched terms overlap: AGE-RAGE, Sphingolipid, and Fc Epsilon RI signaling pathways as well as long term potentiation (Extended data, Workbook 5, sheet 518).\n\n(A) Risk factors enrichment network. In the network the color gradient indicates the proportion of genes in each cluster associated with the enriched GO term. Dark blue nodes include dopaminergic synapse and pathways related to the reward system. Cyan nodes include the AGE-RAGE Signaling pathway in diabetic complications, immune system pathways and lipid signaling. Magenta nodes involve terms associated with immune system function and also insulin signaling. (B) GO pathway terms and associated genes. Bar graph showing the percentage of genes connected with the GO terms. Bars are colored according to the network (Figure 3A).\n\nA protein-protein interaction network revealed the insulin connection between the LRRK2 and HLA-DQB1 networks using the multiple protein option in the STRING database (Figure 4A, Extended data, Workbook 6, sheets 1–224). The distribution for the PPI scores for each show that the majority of the interactions fall in the high range with scores between 0.7 and 1.0 (Figure 4B). Insulin (INS) and its receptor (INSR) are connected to HLA-DBQ1 through 1st shell interactions both of which are based on crystallographic evidence. INSR is in turn connected to CALM1, a calmodulin binding protein involved in calcium signaling and associated with diverse processes including circadian entrainment (KEGG pathway 04713). The evidence for the INSR/CALM1 interaction is based on coimmunoprecipitation, electro mobility shift, and western blot assays. Relevant interactions, scores, and references are provided in Table 1.\n\n(A) PPI network showing the insulin interaction with the Narcolepsy gene (HLA-DQB1) and Parkinson's disease gene (LRRK2.) (B) Interaction score distribution, X-axis, interaction score; Y-axis, frequency.\n\nIn the network, CALM1 bridges INSR, CAMK1D (the only common gene among the database curated genesets for PD, narcolepsy, and IR), and LRRK2. The CALM1 and CAMK1D relationship is supported by coimmunoprecipitation and filter binding and phage display assays. The CALM1/LRRK2 interaction is supported by cosedimentation, coimmunoprecipitation and genetic interference assays.\n\nThere are many proteins in the network related to insulin signaling (IDE, IGF1, IGF1R, INSRR, YWHAH, YWHAG, PRKCE, KCNN2, INS-IGF2, RAF1, CACNA1C, CALM1, CALM2, CALM3, KCNN2, PRKCE). Several genes are implicated in AD (CACNA1C, CALM1, CALM2, CALM3, IDE), circadian entrainment (CACNA1C, CALM1, CALM2, CALM3), and dopamine signaling (CACNA1C, CALM1, CALM2, CALM3, LRRK2). LRRK2 is the only gene in the network linked to PD. There were no experimentally validated interacting partners for HCRT and it did not connect to the network.\n\n\nDiscussion\n\nThe aim of this study is to identify the underlying genes and pathways linking PD, narcolepsy, and IR. An integrative genomics and systems biology approach was used for the analysis of gene expression patterns of the LRRK2, HLA-DQB1, and HCRT genes which are strongly associated with each of these disorders. A comparison of the shared gene correlates for sleep, neurodegeneration, behavior, and insulin led to the identification of genes such as CACNA1C, BHLHE41, HMGB1, and CAMK1D whose defects might be plausible for the narcoleptic-like symptoms in PD and the relationship with IR.\n\nIn addition to the PD- and insulin-related enrichment terms for the HLA-DQB1 correlates resulting from the cluster analysis, a large number of highly significant genes and terms associated with olfactory processes and keratinocytes/keratin were obtained. The olfaction related genes identified here may be relevant to PD because PD involves degeneration of the olfactory system, which often begins with an impaired sense of smell30. Moreover, diabetes has also been linked to olfactory dysfunction31. There is also evidence supporting a link between PD and keratinocytes and keratin. In a study that considered the effects of PD on non-neuronal tissues, it was reported that individuals with PD had a higher incidence of melanoma and non-melanoma skin cancers32. Interestingly, a link with diabetes and keratinocytes and keratin is most evident in the slow rate of wound healing attributed to high blood glucose levels33.\n\nThe PPI network of LRRK2, HLA-DQB1, and CAMK1D reveals a connection with several insulin/diabetes, circadian, and PD risk factor genes supporting our hypothesis that these three disorders have common pathogenetic processes, further supporting other studies that have reported a relationship between them. Moreover, gene variants of narcolepsy-related genes, HLA-DQB1 and CAMK1D, are associated with diabetes, IR, and PD.\n\nThe RAGE signaling pathway, identified here through GO enrichment of the shared genesets, may be central to connecting PD and IR. RAGE is associated with the pathogenesis of several disorders, including diabetes, via inflammation. RAGE is also highly expressed in PD patients when compared with age-matched controls. RAGE gene variants have been linked to sporadic PD in an Asian population34,35, indicating that RAGE might play a role in the pathogenesis of PD. Moreover, silencing of the RAGE pathway in a mouse model of PD improved neuroinflammation which causes dopaminergic neurodegeneration in PD patients36. This is important because the deterioration of dopaminergic neurons in the brain is believed to play a critical role in the development of PD37. By the time clinical signs of PD are identified and a diagnosis is made, a large number of dopaminergic neurons are already lost1. Dopaminergic neurons are also involved in promoting feeding behavior in the hypoglycemic state which is mediated by insulin receptors in the substantia nigra, indicating that dopaminergic neuronal loss may alter glycemic control38,39. Loss of orexin/hypocretin is also linked to binge-eating behavior, low BMR, and obesity, which is also a symptom of narcolepsy. In addition, type 2 diabetes is strongly associated with an increased risk of PD.\n\nAdditional insight into the relationship between these disorders is evident from studies in which the repurposing of treatment for one of these diseases has been used to alleviate symptoms in another. Results from a recent clinical trial in which PD patients were treated with intranasal insulin, reported that test subjects had improved verbal fluency and motor skills and sleep related symptoms40. Melatonin, the naturally occurring hormone that controls sleep and wake cycles, was also found to be beneficial in PD41.\n\nThere are more than 10 million people worldwide that live with Parkinson's disease. Additional studies aimed at identifying genes and regulatory factors underlying and bridging these comorbid disorders may aid in the design of early intervention and diagnosis strategies, as well as treatment regimes for patients with PD, diabetes, and/or narcolepsy.\n\n\nConclusion\n\nWe have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: Extended data workbook 1 LRRK2, HLA-DQB1, and HCRT gene correlates.xlsx. https://doi.org/10.6084/m9.figshare.13072037.v117.\n\nThis file contains gene correlates of LRRK2, HLA-DQB1 and HCRT in the hypothalamus, dorsal thalamus, pons and nucleus subcoeruleus.\n\nFigshare: Extended data workbook 2 Cluster analysis of gene correlates.xlsx. https://doi.org/10.6084/m9.figshare.13072103.v119.\n\nThis file contains cluster analysis of gene correlates of LRRK2, HLA-DQB1 and HCRT in the hypothalamus, dorsal thalamus, pons and nucleus subcoeruleus.\n\nFigshare: Extended data workbook 3 Common genes and functions.xlsx. https://doi.org/10.6084/m9.figshare.13072124.v120.\n\nThis file contains gene set overlap and functional analysis for LRRK2, HLA-DQB1, and HCRT gene correlates.\n\nFigshare: Extended data workbook 4 Keyword genes.xlsx. https://doi.org/10.6084/m9.figshare.13072130.v121.\n\nThis file contains keyword enrichment of gene correlates of LRRK2, HLA-DQB1 and HCRT.\n\nFigshare: Extended data workbook 5 PD, narcolepsy and IR risk factors genes.xlsx. https://doi.org/10.6084/m9.figshare.13072151.v118.\n\nThis file contains Parkinson's disease, narcolepsy and Insulin resistance risk factors genes\n\nFigshare: Extended data workbook 6 LRRK2, HLA-DQB1 and CAMK1D protein-protein interaction network.xlsx. https://doi.org/10.6084/m9.figshare.13072160.v124.\n\nThis file contains LRRK2, HLA-DQB1 and CAMK1D protein-protein interaction network coordinates.\n\nExtended data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
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Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072037.v1\n\nDelprato A: Extended data workbook 5 PD, narcolepsy and IR risk factors genes.xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072151.v1\n\nDelprato A: Extended data workbook 2 Cluster analysis of gene correlates.xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072103.v1\n\nDelprato A: Extended data workbook 3 Common genes and functions.xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072124.v1\n\nDelprato A: Extended data workbook 4 Keyword genes.xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072130.v1\n\nXue A, Wu Y, Zhu Z, et al.: Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018; 9(1): 2941. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJin X, Li J, Li W, et al.: Weighted gene co-expression network analysis reveals specific modules and biomarkers in Parkinson's disease. Neurosci Lett. 2020; 728: 134950. PubMed Abstract | Publisher Full Text\n\nDelprato A: Extended data workbook 6 LRRK2, HLA-DQB1 and CAMK1D protein-protein interaction network.xlsx. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13072160.v1\n\nMenting JG, Whittaker J, Margetts MB, et al.: How insulin engages its primary binding site on the insulin receptor. Nature. 2013; 493(7431): 241–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPausch MH, Kaim D, Kunisawa R, et al.: Multiple Ca2+/calmodulin-dependent protein kinase genes in a unicellular eukaryote. EMBO J. 1991; 10(6): 1511–22. PubMed Abstract | Free Full Text\n\nLee KH, Wucherpfennig KW, Wiley DC: Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol. 2001; 2(6): 501–7. PubMed Abstract | Publisher Full Text\n\nKim HS, Jung MS, Lee K, et al.: An S-locus receptor-like kinase in plasma membrane interacts with calmodulin in Arabidopsis. FEBS Lett. 2009; 583(1): 36–42. PubMed Abstract | Publisher Full Text\n\nMeixner A, Boldt K, Van Troys M, et al.: A QUICK screen for Lrrk2 interaction partners--leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. Mol Cell Proteomics. 2011; 10(1): M110.001172. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoty RL, Hawkes CH, Berendse HW: Olfactory dysfunction in Parkinson's disease and related disorders. In: Halliday, PhD G, Barker, MRCP, PhD R, Rowe, FRACP, PhD D, editors. Non-dopamine Lesions in Parkinson's Disease. Oxford University Press; 2010; 65–91.\n\nZaghloul H, Pallayova M, Al-Nuaimi O, et al.: Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions. Diabet Med. 2018; 35(1): 41–52. PubMed Abstract | Publisher Full Text\n\nPlanken A, Kurvits L, Reimann E, et al.: Looking beyond the brain to improve the pathogenic understanding of Parkinson's disease: implications of whole transcriptome profiling of Patients’ skin. BMC Neurol. 2017; 17(1): 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSpravchikov N, Sizyakov G, Gartsbein M, et al.: Glucose effects on skin keratinocytes: implications for diabetes skin complications. Diabetes. 2001; 50(7): 1627–35. PubMed Abstract | Publisher Full Text\n\nGuerrero E, Vasudevaraju P, Hegde ML, et al.: Recent advances in α -synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease. Mol Neurobiol. 2013; 47(2): 525–36. PubMed Abstract | Publisher Full Text\n\nGao J, Teng J, Liu H, et al.: Association of RAGE gene polymorphisms with sporadic Parkinson's disease in Chinese Han population. Neurosci Lett. 2014; 559: 158–62. PubMed Abstract | Publisher Full Text\n\nWang X, Sun X, Niu M, et al.: RAGE Silencing Ameliorates Neuroinflammation by Inhibition of p38-NF-κ B Signaling Pathway in Mouse Model of Parkinson's Disease. Front Neurosci. 2020; 14: 353. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMamelak M: Parkinson's disease, the dopaminergic neuron and gammahydroxybutyrate. Neurol Ther. 2018; 7(1): 5–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSergi D, Renaud J, Simola N, et al.: Diabetes, a contemporary risk for Parkinson's disease: epidemiological and cellular evidences. Front Aging Neurosci. 2019; 11: 302. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFiory F, Perruolo G, Cimmino I, et al.: The relevance of insulin action in the dopaminergic system. Front Neurosci. 2019; 13: 868. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIntranasal Insulin May Ease Parkinson's Cognitive and Motor Symptoms, Early Study Shows n.d. (accessed September 7, 2020). Reference Source\n\nPandi-Perumal SR, BaHammam AS, Brown GM, et al.: Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res. 2013; 23(3): 267–300. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "77250",
"date": "08 Feb 2021",
"name": "Makoto Hashimoto",
"expertise": [
"Reviewer Expertise neurodegenerative 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\nComorbidity of Parkinson’s disease (PD) with insulin resistance (IR) and narcolepsy-like sleep patterns are frequently described, but the mechanism is unclear.\n\nIn this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy to identify genes and pathways that may shed light on how these disorders are interrelated. The results showed that the PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR were shown to be CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. The authors concluded that these findings might aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy. Overall, the results are interesting and clear. I agree that the paper may contribute to the PD research. My comments are as follows:\nIt would be much better if modification of the expression of the identified genes (knockout or overexpression), including CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE, might result in phenotypes related to PD and/or narcolepsy in cells or animal models. Are there such previous papers? Otherwise, the result of network analysis alone seems preliminary.\n\nIn the same context, other experiments, such as immunohistochemistry, should be conducted to confirm the expression of these genes at the protein 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? Partly",
"responses": [
{
"c_id": "6429",
"date": "11 Mar 2021",
"name": "Anna Delprato",
"role": "Author Response",
"response": "We would like to thank you for taking the time to review our article and providing constructive feedback. We will submit a revised version once we have received all of the reviews."
},
{
"c_id": "7231",
"date": "20 Oct 2021",
"name": "Anna Delprato",
"role": "Author Response",
"response": "Reviewer 1 Comorbidity of Parkinson’s disease (PD) with insulin resistance (IR) and narcolepsy-like sleep patterns are frequently described, but the mechanism is unclear. In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy to identify genes and pathways that may shed light on how these disorders are interrelated. The results showed that the PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR were shown to be CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. The authors concluded that these findings might aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy. Overall, the results are interesting and clear. I agree that the paper may contribute to the PD research. My comments are as follows: Reviewer 1 comment: It would be much better if modification of the expression of the identified genes (knockout or overexpression), including CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE, might result in phenotypes related to PD and/or narcolepsy in cells or animal models. Are there such previous papers? Otherwise, the result of network analysis alone seems Preliminary. Response: We thank the reviewer for taking the time to provide us constructive feedback on this manuscript. There is in fact a great deal of evidence derived from knockout and cell based studies linking CACNA1C, HMGB1, and AGER/AGE-RAGE to Parkinson's pathogenesis. CACNA1C is also associated with Circadian rhythm and narcolepsy. In addition, CAMK1D is a component of the calmodulin dependent calcium signaling cascade and there is also support for its role as an interactor of LRRK2, one of the key genes influencing Parkinson’s. HMGB1 and AGER/AGE-RAGE appear to act in concert mediating inflammatory processes that ultimately lead to neuron cell death via NF-κB signaling. AGER/AGE-RAGE and LRRK2 are also linked as RAGE proteins are upregulated in LRRK2 G2019S mutant cells. The LRRK2 G2019S mutation is the most common genetic cause of neurodegeneration and PD. The other major gene of interest identified in the ppi network, BHLHE41, is a transcription factor associated with Circadian processes. Variants of BHLHE41 have been implicated in short sleep syndrome and this gene also has a role in immune function. BHLHE41 in addition to CAMK1D, RAGE, and HMGB1 are also implicated in diabetes. Details of the supporting studies for the candidate genes as well as the other network genes have been included in the Introduction and Discussion sections of the revised manuscript. Reviewer 1 comment: In the same context, other experiments, such as immunohistochemistry, should be conducted to confirm the expression of these genes at the protein level. Response: We agree that the above mentioned studies could be useful to further support the results presented here. Regrettably we do not have access to wet lab facilities. Our method of research is based in bioinformatics, systems biology and integrative genomics. However, we were able to address your question using legacy datasets from the Human Protein Atlas (https://www.proteinatlas.org/) which also contains data for gene expression in mice and pigs and the human database in the Allen Brain Atlas (https://human.brain-map.org/microarray/search). Results for gene expression of the key genes in the hypothalamus and pons are as follows: Each of the genes with the exception of AGER were expressed in both the hypothalamus and pons for human, mouse and pig. CACNA1C expression was also confirmed at the protein level by immunocytochemistry in the mouse hypothalamus and pons/medulla. The expression pattern of the key genes in dorsal thalamus and subcoeruleus nucleus data were obtained for humans only and are as follows: HMGB1, AGER, BHLHE41 are expressed in both the dorsal thalamus and subcoeruleus nucleus. CACNA1C is expressed in the dorsal thalamus and is not expressed in the subcoeruleus nucleus CAMK1D was not expressed in either the dorsal thalamus or subcoeruleus nucleus. These data are have been added to the revised version of the manuscript."
}
]
},
{
"id": "82398",
"date": "12 Apr 2021",
"name": "Qing Wang",
"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 study has identified the genes such as CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE that link PD with narcolepsy and insulin resistance and their signaling networks are connected through insulin and immune system pathways. These findings may contribute to develop new treatment strategies in PD patients as well as individuals with diabetes and narcolepsy. The results of the study are interesting.\nHowever, the introduction and discussion are too weak. So it is suggested to cite more relevant references as follows (please see the reference list below) in order to elaborate on the mechanisms.\n\nAfter my concerns above have been fully addressed, I am happy to re-evaluate this 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?\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": "7232",
"date": "20 Oct 2021",
"name": "Anna Delprato",
"role": "Author Response",
"response": "Reviewer 2 This study has identified the genes such as CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE that link PD with narcolepsy and insulin resistance and their signaling networks are connected through insulin and immune system pathways. These findings may contribute to developing new treatment strategies in PD patients as well as individuals with diabetes and narcolepsy. The results of the study are interesting. Reviewer 2 comment: However, the introduction and discussion are too weak. So it is suggested to cite more relevant references as follows (please see the reference list below) in order to elaborate on the mechanisms. After my concerns above have been fully addressed, I am happy to re-evaluate this manuscript. Response: We thank the reviewer for providing us with many relevant references. Based on this information we have revised the Introduction and Discussion sections of the manuscript and have included more mechanistic detail and context as recommended."
}
]
},
{
"id": "83029",
"date": "06 May 2021",
"name": "Daniel Enterría-Morales",
"expertise": [
"Reviewer Expertise Neurodegeneration",
"Parkinson's disease",
"Neurochemistry."
],
"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\nParkinson’s disease is the second most common neurodegenerative disease right after Alzheimer’s disease nowadays. There is no treatment to counteract the symptoms of the disease, and most of the medications used are aimed at alleviating the symptoms. However, the use of these drugs also has disadvantages in the form of side effects, which makes the quality of life of the patients drop drastically. Lately, research on Parkinson's disease has been focused on the detection of markers that allow diagnosis of this disorder in early stages to increase the probabilities of treatments being effective. Within these types of studies, we have this article published by Chunduri et al., in which the main objective is the search for the expression of certain genes shared between Parkinson's disease, insulin resistance and narcolepsy. The authors propose to analyze the molecular bases of the comorbidity of these three disorders in order to find risk factors that could predispose and facilitate the early diagnosis of Parkinson's disease. As a result of the study, the authors have identified several genes that are related to the signaling pathways of dopamine, insulin and the immune system, among which are: CACNA1C, CAMK1D, BHLHE41, HMGB1, and the AGE-RAGE axis.\nThe preliminary data obtained in this study is interesting and would allow further research on the early diagnosis of this disorder, through the individualized study of each of these candidate genes, probably through knock-out or knock-down strategies in animal models. However, some parts of the article need to be supplemented with additional data, and furthermore, the discussion of the data obtained seems short and incomplete, so the authors should increase the number of bibliographic references that are currently discussing the analysis of comorbidity in Parkinson's disease, both in animal models and in humans.\nSpecifically, I would like the authors to address the following points:\nIt would be appropriate to validate the expression of some of these candidate genes in the mentioned brain regions, in the tissue of healthy human or wild-type animals (e.g. mouse, rat, monkey), mainly by quantitative PCR or in situ hybridization, or alternatively by Western Blot or immunohistochemistry. It would be very interesting if the authors could also analyze the expression of these genes in tissue from patients or animal models of Parkinson's disease.\n\nIt would be quite useful to validate the data obtained in humans, with the gene expression database available for mouse or monkey brain tissue, on the Allen Brain Institute website. Mouse Brain Atlas: https://developingmouse.brain-map.org/search/index Non-human primate Brain Atlas: https://www.blueprintnhpatlas.org/microarray/search\n\nIt would be great if the authors could comment on why they decided to analyze specifically the comorbidity of Parkinson’s disease with insulin resistance and narcolepsy. There are other disorders that are more frequent comorbidities in Parkinson’s disease patients, such as hypertension, Crohn's disease, schizophrenia, restless leg syndrome, anemia (see attached references).1,2,3\n\nCould the authors comment and discuss if some of the candidate genes found are expressed in dopaminergic neurons in the human or mouse brain (regarding the bibliography available in the field)?\n\nI suggest that the authors should cite more relevant references in the discussion section (see list of references attached).4,5,6,7,8,9,10,11,12,13,14,15,16,17\n\nOnce the authors are able to address all the issues I have proposed in this report, I would be willing to re-evaluate this 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? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7233",
"date": "20 Oct 2021",
"name": "Anna Delprato",
"role": "Author Response",
"response": "Reviewer 3 Parkinson’s disease is the second most common neurodegenerative disease right after Alzheimer’s disease nowadays. There is no treatment to counteract the symptoms of the disease, and most of the medications used are aimed at alleviating the symptoms. However, the use of these drugs also has disadvantages in the form of side effects, which makes the quality of life of the patients drop drastically. Lately, research on Parkinson's disease has been focused on the detection of markers that allow diagnosis of this disorder in early stages to increase the probabilities of treatments being effective. Within these types of studies, we have this article published by Chunduri et al., in which the main objective is the search for the expression of certain genes shared between Parkinson's disease, insulin resistance and narcolepsy. The authors propose to analyze the molecular bases of the comorbidity of these three disorders in order to find risk factors that could predispose and facilitate the early diagnosis of Parkinson's disease. As a result of the study, the authors have identified several genes that are related to the signaling pathways of dopamine, insulin and the immune system, among which are: CACNA1C, CAMK1D, BHLHE41, HMGB1, and the AGE-RAGE axis. The preliminary data obtained in this study is interesting and would allow further research on the early diagnosis of this disorder, through the individualized study of each of these candidate genes, probably through knock-out or knock-down strategies in animal models. However, some parts of the article need to be supplemented with additional data, and furthermore, the discussion of the data obtained seems short and incomplete, so the authors should increase the number of bibliographic references that are currently discussing the analysis of comorbidity in Parkinson's disease, both in animal models and in humans. Reviewer 3 comment: Specifically, I would like the authors to address the following points: It would be appropriate to validate the expression of some of these candidate genes in the mentioned brain regions, in the tissue of healthy human or wild-type animals (e.g. mouse, rat, monkey), mainly by quantitative PCR or in situ hybridization, or alternatively by Western Blot or immunohistochemistry. It would be very interesting if the authors could also analyze the expression of these genes in tissue from patients or animal models of Parkinson's disease. Response: We have addressed the request for validation of candidate gene expression in the mentioned brain regions above in our response to Reviewer 1 and have added the information to the Results and Discussion sections of the revised manuscript. To summarize our findings, each of the key genes is expressed in at least two of the brain regions relevant to this study. To address the reviewer’s question concerning expression of these genes in tissue from patients or animal models of Parkinson's disease, we have analyzed the gene expression data available in the NCBI GEO database specifically for Parkinson’s Disease datasets to determine if any of the key genes identified in our study are differentially expressed. Out of 24 available datasets, we found that BHLHE41 and AGER were differentially expressed as compared with controls from two distinct studies (https://www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE36321 and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE19587). For BHLHE41, the study involved assessing gene expression in human neural stem cells containing the LRRK2 (G2019S) pathogenic mutation. The LRRK2 (G2019S) containing cells had higher expression of BHLHE4. AGER was differentially expressed with borderline significance in a study that examined post mortem medullary regions from brains with evidence of Parkinson’s. AGER was expressed higher in brains from individuals with Parkinson’s. However, due to low n values we do not have enough confidence in the data to include these results in the manuscript. The other genes of interest, CACNA1C, CAMK1D, and HMGB1 were not identified in any of the GEO gene expression datasets as being expressed differently than controls. We also assessed expression of the key genes in individuals with Parkinson’s versus a healthy control group from data generated in a longitudinal study in which the aim is to identify biomarkers of Parkinson’s disease progression (Parkinson's Progression Markers Initiative https://www.ppmi-info.org/). The Parkinson’s cohort consisted of 423 individuals and the control group, 196. There was no difference in the expression for any of the key genes. Reviewer 3 comment: It would be quite useful to validate the data obtained in humans, with the gene expression database available for mouse or monkey brain tissue, on the Allen Brain Institute website. Mouse Brain Atlas: https://developingmouse.brain-map.org/search/index Non-human primate Brain Atlas: https://www.blueprintnhpatlas.org/microarray/search Response: Thank you for the suggestion. However, to the best of our knowledge, there is no Microarray data available for mouse at the Allen Brain Atlas but we were able to consider the in situ hybridization data (discussed above). Regrettably the Non-human primate atlas does not contain data for the relevant brain regions used in this study which is unfortunate because this is an intriguing dataset. Reviewer 3 comment: It would be great if the authors could comment on why they decided to analyze specifically the comorbidity of Parkinson’s disease with insulin resistance and narcolepsy. There are other disorders that are more frequent comorbidities in Parkinson’s disease patients, such as hypertension, Crohn's disease, schizophrenia, restless leg syndrome, anemia (see attached references).1,2,3 Response: Initially, the focus of our study was to investigate the connection between Parkinson’s and narcolepsy. Early on in the data collection and preliminary analysis, we observed that many of the gene correlates were linked to insulin resistance. On the basis of this finding we decided to expand the scope of the study. Reviewer 3 comment: Could the authors comment and discuss if some of the candidate genes found are expressed in dopaminergic neurons in the human or mouse brain (regarding the bibliography available in the field)? Response: AGER, BHLHE41, CACNA1C, and HMGB1 are expressed in Dopaminergic neurons from the substantia nigra pars compacta and ventral tegmental area in rats. These data are publicly accessible at GEO datasets, accession number: GSE1837 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1837). There is also further support from previously published studies: CACNA1C (PTSD study generated mice with specific deletion of cacna1c from D1R-expressing neurons https://pubmed.ncbi.nlm.nih.gov/32332995/). CAMK1D (Decreased mRNA Expression of Key ER Ca2+ Regulators and CamK1D in LRRK2 G2019S NeuronsD https://www.sciencedirect.com/science/article/pii/S2213671118304909) HMGB1/RAGE/AGER (Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation https://pubmed.ncbi.nlm.nih.gov/28887039) Reviewer 3 comment: I suggest that the authors should cite more relevant references in the discussion section (see list of references attached).4,5,6,7,8,9,10,11,12,13,14,15,16,17 Response: We thank the reviewer for providing these references. We have updated the Introduction and Discussion sections of the revised manuscript to include this information."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1361
|
https://f1000research.com/articles/10-586/v1
|
16 Jul 21
|
{
"type": "Research Article",
"title": "Frequency of parasitic infections in Arachishypogaea L (groundnuts), Citrulluslanatus seeds (watermelon seeds), and Ziziphusspina-christi (nabag) sold by street vendors in Khartoum State, Sudan: a cross-sectional study",
"authors": [
"Arwa Suleiman Mohammed",
"Ahmed Abd Alla",
"Ahmed Galander",
"Tayseer Elfaki",
"Ahmed Ibrahim Hashim",
"Hisham N. Altayb",
"Arwa Suleiman Mohammed",
"Ahmed Galander",
"Tayseer Elfaki",
"Ahmed Ibrahim Hashim",
"Hisham N. Altayb"
],
"abstract": "Background: Plant products, including seeds are an important source of vitamins, minerals, proteins, and energy. This study aimed to assess parasitic contaminations in roasted groundnuts, nabag, and tasali (watermelon seeds) sold by street vendors in Khartoum State, Sudan. Methods: The frequency of parasitic contaminations among all crop products was detected by washing the plants with saline, and then conducting an examination using a formal ether concentration technique (FECT), followed by a saturated sugar floatation technique. Results: The detected parasites belonged to two species: Entamoeba histolytica (33.3%) and Giardia lamblia (15.6%). No helminthic parasites were detected. Mixed contamination of the mentioned parasites was also observed (11.1%). The most contaminated crop was nabag, followed by groundnut, and finally tasali. Conclusion: No relation was established between the positivity of samples for parasites and crop type, Khartoum State city, or seller sex. FECT was more sensitive than the saturated sugar floatation technique as a detection method.",
"keywords": [
"Arachis hypogaea L",
"Groundnuts",
"Citrullus lanatus",
"Nabag",
"Tasali"
],
"content": "Introduction\n\nIntestinal parasitic infections can be transmitted orally through the ingestion of infective agents from infected food, water, or contaminated hands.1,2 Food contamination and food borne parasitic diseases frequently occur globally. These are estimated to amount to 23.2 million cases and 45,927 deaths annually.3 Fresh fruits and vegetables could be a source of dissemination of foodborne parasitic diseases.4,5 A study in Ghana revealed Ascaris lumbricoides (roundworm), Ancylostoma duodenale (nematode), Necator americanus (hookworm), and Strongyloides stercoralis (threadworm) contaminations in tiger nuts.6 Another study on tiger nuts reported other contaminants such as animal droppings, fungi toxins and bacteria.7 Groundnuts, Ziziphus spina-christi (nabag), and watermelon seeds (tasali) are widely consumed in Africa and the Middle East.8 Nabag and tasali are widely eaten in Sudan.\n\nThese crops are natural sources of carbohydrates, proteins, fats, -iron, calcium, ascorbic acid, thiamine, riboflavin, and niacin.9-12 Groundnuts in Sudan are mainly used for oil extraction, but can be eaten as a snack: raw, or after roasting without its external cortex envelop.13 Nabag is eaten after the sweet pulp of the fruit is dried to produce fine flour.14 The flour is placed in small metal cups and steamed. Dried pulp flour and water are also mixed with sesame and shaped into small balls.15 Fruit pulp prepared in these two ways can be consumed either immediately or stored for future use. In addition to groundnuts, nabag, and tasali,16 many crop products represent an important and for some, the only source of income in Sudan.15\n\nIntestinal parasitic infections are very common worldwide. They are often not diagnosed and hence not treated, leading to harmful effects which can be lethal in some cases. Food contamination may occur when food is prepared, stored, or handled; this is a common phenomenon in public places like the streets.15 Identifying parasitic contamination will help fight these infections, because knowing contamination rates allows to take the necessary preventive measures. The objective of this study was to identify parasitic contamination rates in Arachis hypogaea L (groundnuts), Citrullus lanatus seeds (watermelon seeds), and Ziziphus spina-christi (nabag) sold by street vendors in Khartoum State, in Sudan.\n\n\nMethod\n\nThis descriptive cross-sectional study was conducted between July and October 2019 in Khartoum State, Sudan. The study included the Khartoum cities Khartoum, Bahri, and Omdurman.\n\nEthical approval for this study was received from the Sudan University of Science and Technology’s Committee of Medical Laboratory Science, with the ethical approval number (MLS – IEC – 03 – 18). All participants in this study issued written informed consent for participation and data publication; for participants under 18 years old, consent was obtained from their guardians.\n\nThe study was conducted on street vendors in Khartoum State, sampling groundnuts, nabag, and tasali. In total, 69.8 g of nabag, 50 g of tasali, and 69.9 g of groundnuts were purchased from 15 sellers in Sudan’s Khartoum state (five sellers from each city of interest, i.e. Bahri, Khartoum, and Omdurman), using a cluster random sampling technique, for a total of 45 samples (15 samples from each crop product type). The items were brought to the laboratory and tested under a microscope for parasitic agents. Sellers’ location, gender, and age group were observed.\n\nEach product purchased from the same seller was put separately in clean, dry glass bottles after labelling, which were thenfilled up to the surface with distilled water. Bottles were left for one hour, and then the nabag, tasali, and groundnut were removed from the liquid using a plastic sieve; the washes were collected and then examined using a formal ether concentration technique (FECT) and saturated sugar floatation technique.\n\nNabag and tasali washes were added to 4 ml of 10% volume per volume formal saline contained in a conical centrifuge tube. The contents were well-mixed by centrifuging for 20 seconds. After centrifugation four layers of ether, plant debris, formal saline, and deposit were discarded using a sterile plastic Pastier pipette. The deposits of sieved wash liquid were then examined under a microscope using 10× and 40× magnification, to detect parasitic agents such as cysts,trophozoite larva, helminth eggs, and species including G lamblia, E histolytica, A lumbercoides, E. vermicuaris, T. trichiura, A. duodenale, N. americanus and S. stercoralis).17\n\nApproximately 1 ml of each previously prepared crop wash was put into a glass tube; then, the floatation solution (saturated sugar) was added gradually until a convex surface was formed on the top of the glass tube, which was then covered with a glass cover. The tube was left for 15–30 min, after which the glass cover was removed; the solution was put on a microscope slide, and examined under the microscope to detect parasitic agents.17\n\nThe statistical package for social science (SPSS, IBM) version 20 program, was used for data analysis. Statistical tests were performed at a 5% significance level (P < 0.05) and a confidence interval (CI) of 95%. The measured frequencies were computed. The statistical significance of relationships between variables was determined using Pearson’s Chi-squared test.\n\n\nResults\n\nThe participants in this study were 15 street vendors selling groundnuts, nabag, and tasali. The population was divided into six age groups: 10–20, 21–30, 31–40, 41–50, 51–60, and over 61 years. The most common age group was 31–40 (46.7%), followed by 41–50 (20%), 21–30 (13.3%), 10–20 (6.7%), 51–60 (6.7%), and more than 61 (6.7%). Eight (53.3%) of the 15 subjects were women, while seven (46.7%) were men.\n\nThe total parasitic contamination rate was 60% (27 samples), divided as follows: 20% (n = 9) for groundnut, 22.2 % (n = 10) for nabag, and 17.8 % (n = 8) for tasali. A Chi-squared test was used to test the relationship between crop type and detection of parasites, revealing an insignificant relationship with P = 0.757 (Table 1). The presence of both E. histolytica and G. lamblia accounted for 11.1% of the positive results.\n\nThe contamination rate assessed using FECT was 53.3% (24 samples), while the sugar floatation technique detected a contamination rate of 48.9% (21 samples); the correlation between detection and technique used was found to be highly significant at P = 0.000 (Table 2). Using FECT, the detected prevalence of E. histolytica, G. lamblia, and mixed contamination of E. histolytica and G. lamblia were 33.3% (15), 11.1% (5), and 8.9% (4), respectively; when using the sugar floatation technique, the detected prevalence of E. histolytica, G. lamblia, and mixed contamination of E. histolytica and G. lamblia were 37.8% (17), 8.9% (4), and 2.2% (1), respectively (Table 2). The prevalence rates of E. histolytica in groundnuts, nabag, and tasali were 15.6% (7), 8.9% (4), and 8.9% (5), respectively, and for G. lamblia were 2.2% (1), 6.7% (3), and 6.7% (3) (Table 3). Mixed contamination was found in groundnuts, nabag, and tasali in the following proportions: 2.2% (1), 6.7% (3), and 2.2% (1), respectively. Contamination rates for groundnut, nabag, and tasali detected by FECT were 20% (9), 20% (9), and 13.3% (6), respectively, while those detected using the sugar floatation technique were 20% (9), 13.3 % (6), and 15.5% (7).\n\nThe relationship between crop type positivity to contamination and technique used was negligible for both FECT (P = 0.655) and sugar floatation technique (P = 0.591) (Table 4). The 31-40 age group had the highest contamination rate (33.3%), followed by 41–50 (13.3%), more than 61+ (6.7%), 51–60 (4.4%), 21–30 (2.2%), and 10–20 (0%) groups. There was a significant association between seller age group and outcome positivity (P = 0.028). Contamination rates were 24.4%, 20%, and 15.6% in Khartoum state cities, i.e. Khartoum, Bahri, and Omdurman, respectively. There was no relation between city and contamination rate (P = 0.329). The results revealed that E. histolytica was the dominant parasite across all city, with prevalence rates of 17.8%, 17.8%, and 8.9 % in Khartoum, Bahri, and Omdurman, respectively; while G. lamblia had lower prevalence rates in Khartoum, Bahri, and Omdurman, at 13.4%, 4.4%, and 8.9%, respectively. Relationship testing between city and species detected yielded insignificant results (P = 0.460).\n\n\nDiscussion\n\nGroundnut and watermelon seeds are important cash crops. They respectively represented 43,532 USD (59,620 tons) and 49,355 USD (74,149 tons) of Sudanese exports in 2018.18 To the best of our knowledge, this study was the first to look into the parasitic contamination of groundnuts, nabag, and tasali sold by Sudanese street vendors. Two studies in Ghana and Nigeria estimated parasitic infections in the root plant Cyperus esculentus L. (tiger nuts); those studies were similar to some degree, and found contamination to be significant.6,7 The overall contamination rate in the previous study was 60%, which is considered significant. This rate was expected, because vendors sold their products unprotected and handled them with their bare hands. Contamination does not necessarily happen at the selling stage; it can happen during crop farming, harvesting, storage and transport, and even at home, according to Idahosa, 201119 and Porter et al., 1990.20 Contamination may occur during the planting phase as a result of polluted irrigational water, as mentioned by Keraita et al., 2002,21 which is contaminated as a result of inadequate or insufficient sanitation infrastructures to cope with the rate of urbanization.22 In our study, the most contaminated crop was nabag (22.2%), followed by groundnut (20%), and finally tasali. This may be due nabag being sold raw, which also exposes it to the previously mentioned contamination factors, particularly during the growing and harvesting phases; When nuts fall to the ground, they may come into contact with potentially polluted soil, as well as other external contaminants carried by wind, humans, or animals.\n\nHowever, because groundnuts grow beneath the soil surface,13 they might be damaged if the nuts comes into contact with soil that has been contaminated, or with polluted irrigational water.\n\nDespite this, salting and roasting may help to reduce contamination. Tasali had the lowest contamination rate in comparison to others. This could be explained by it being protected by the fruit (watermelon) during growing and harvesting, as well as the washing, salting, and roasting processes that occur before it is eaten. In our study, the parasites detected belonged to two species: E. histolytica (44.4%) and G. lamblia (26.7%). E. histolytica was the most common of both in all sampled crops (groundnut: 17.8% vs 4.4%, nabag: 15.6% vs 15.6%, and tasali: 11.1% vs 8.9%). Groundnuts had the highest rate of E. histolytica contamination (44.4%). This finding is consistent with a Nigerian study on tiger nuts, which are similar to groundnuts in their cultivation process, and in which E. histolytica was identified as the only protozoan parasite (25% contamination rate).6,7,13 The precise prevalence rates of E. histolytica and G. lamblia in Khartoum State are unknown; however, some studies may help to provide a more concise view. E. histolytica and G. lamblia were found to be common parasites in the following areas: Alhag-yousif (G. lamblia: 46.4% and E. histolytica: 15.50%), Elengaz (G. lamblia: 33.4% and E. histolytica: 3.6%), and Alkalakla (G. lamblia: 33.4% and E. histolytica: 3.6%).17,23,24 These results suggest that contaminated crop products could be a major source of infection.\n\nBetween the saturated sugar floatation technique (prevalence rate: 48.9%) and FECT (prevalence rate: 53.3%), the FECT was the found the most efficient technique for crop examination (P = 0.000). This finding was supported by Abdalazim et al., (2019)17 (P = 0.000). FECT outperformed the saturated sugar floatation technique in detecting both parasites, with FECT detecting 44.2% of E. histolytica and G. lamblia while the sugar floatation technique detected 40% of E. histolytica and 11.1% of G. lamblia. According to our study, seller sex and location (stationed vehicle or no vehicle) did not affect the positivity of crop samples to contamination (P-value: 0.807 and 0.329 respectively), while the age group played a role in the occurrence of contamination.25\n\n\nConclusions\n\nRoasted groundnut, nabag, and tasali that were sold by street vendors in Khartoum State, Sudan were highly contaminated with protozoan parasites. E. histolytica was the dominant parasite in all seeds tested. No connection was found between the crop type and the detected parasite species. Although the rate of contamination for female sellers was higher, the relationship between seller sex and positivity to contamination was not significant. There was no found correlation between the seller’s location and positivity to contamination.\n\n\nData availability\n\nFigshare: Parasitic Contamination Rate of Arachishypogaea L (Groundnuts), Citrulluslanatus Seeds (Watermelon Seeds), and Ziziphusspina-christi (Nabag) Sold by Street Venders in Khartoum State- Sudan. https://doi.org/10.6084/m9.figshare.14397914.v4.25\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nThis work was based on a Master’s dissertation; we thank all members of the Parasitology and Medical Entomology Department, College of Medical Laboratory Science, Sudan University of Science and Technology, whose help was deeply appreciated. Many thanks to Miss. Alaa Mohammed Ahmed Mohammed for her assistance in collecting samples.\n\n\nReferences\n\nGizaw Z, Adane T, Azanaw J, et al.: Childhood intestinal parasitic infection and sanitation predictors in rural Dembiya, northwest Ethiopia. Environ Health Prev Med. 2018 Dec; 23(1): 1–0. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPaniker CJ, Ghosh S: Paniker’s textbook of medical parasitology. JP Medical Ltd; 2017 Sep 14.\n\nTorgerson PR, Devleesschauwer B, Praet N, et al.: World Health Organization estimates of the global and regional disease burden of 11 foodborne parasitic diseases, 2010: a data synthesis. PLoS Med. 2015 Dec 3; 12(12): e1001920. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShahnazi M, Jafari-Sabet M: Prevalence of parasitic contamination of raw vegetables in villages of Qazvin Province, Iran. Foodborne Pathog Dis. 2010 Sep 1; 7(9): 1025–1030. PubMed Abstract | Publisher Full Text\n\nTefera T, Biruksew A, Mekonnen Z, et al.: Parasitic contamination of fruits and vegetables collected from selected local markets of Jimma town, southwest Ethiopia. Int Sch Res Notices. 2014; 2014. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOgban EI, Ukpong IG: Intestinal parasites associated with tiger nuts, Cyperus esculentus L. Calabar Nigeria: Implications for public health. Scholars Acad. J Biosci. 2018; 6(10): 634–638. Publisher Full Text\n\nAyeh-Kumi PF, Tetteh-Quarcoo PB, Duedu KO, et al.: A survey of pathogens associated with Cyperus esculentus L (tiger nuts) tubers sold in a Ghanaian city. BMC Res Notes. 2014 Dec; 7(1): 1–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHegazi GA, Diab MI, Abo El-Fadl RE: In vitro propagation of nabq tree (Ziziphus spina-christi (L.) Desf.). In IX International Symposium on in vitro Culture and Horticultural Breeding . 2016 Mar 13; 1187: 69–78. Publisher Full Text\n\nTorgerson PR, Devleesschauwer B, Praet N, et al.: World Health Organization estimates of the global and regional disease burden of 11 foodborne parasitic diseases, 2010: a data synthesis. PLoS Med. 2015 Dec 3; 12(12): e1001920. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsibuo JY, Akromah R, Safo-Kantanka O, et al.: Chemical composition of groundnut, Arachis hypogaea (L) landraces. African J Biotechnol. 2008; 7(13).\n\nSaied AS, Gebauer J, Hammer K, et al.: Ziziphus spina-christi (L.) Willd.: a multipurpose fruit tree. Genetic Resources and Crop Evolution. 2008 Nov; 55(7): 929–937. Publisher Full Text\n\nTabiri B, Agbenorhevi JK, Wireko-Manu FD, et al.: Watermelon seeds as food: Nutrient composition, phytochemicals and antioxidant activity.2016; 5(2): 139–144. Publisher Full Text\n\nPrasad PV, Kakani VG, Upadhyaya HD: Growth and production of groundnut. UNESCO Encyclopedia. 2010: 1–26.\n\nHussein AS: Ziziphus spina-christi: Analysis of Bioactivities and Chemical Composition. In: Wild Fruits: Composition, Nutritional Value and Products. Springer, Cham; 2019 (pp. 175–197).\n\nSaied AS, Gebauer J, Hammer K, et al.: Ziziphus spina-christi (L.) Willd.: a multipurpose fruit tree. Genetic Resources and Crop Evolution. 2008 Nov; 55(7): 929–937.\n\nGhorai S, Banik SP, Verma D, et al.: Fungal biotechnology in food and feed processing. Food Res Int. 2009 Jun 1; 42(5-6): 577–587. Publisher Full Text\n\nAbdalazim Hassan H, Abd Alla AB, Elfaki TEM, et al.: Frequencies of gastrointestinal parasites among students of primary school in Al Kalakla Locality, Khartoum State, Sudan: a cross-sectional study. F1000Res. 2019 Oct 4; 8: 1719. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFAO: FAO Crop and Food Supply Assesment Mission to the Sudan- Special Report. Rome. 38 pp. Licence:cc BY- NC- SA 3.0 IGO. 2019.\n\nIdahosa OT: Parasitic contamination of fresh vegetables sold in Jos markets. Global J Med Res. 2011 May; 11(1): 21–25.\n\nPorter JD, Gaffney C, Heymann D, et al.: Food-borne outbreak of Giardia lamblia. Am J Public Health. 1990 Oct; 80(10): 1259–1260. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeraita B, Drechsel P, Huibers FP, et al.: Wastewater use in informal irrigation in urban and periurban areas of Kumasi, Ghana. Urban Agriculture Magazine. 2002; 8: 11–13.\n\nAmoah P, Drechsel P, Henseler M, et al.: Irrigated urban vegetable production in Ghana: microbiological contamination in farms and markets and associated consumer risk groups. J Water Health. 2007 Sep; 5(3): 455–466. PubMed Abstract | Publisher Full Text\n\nGabbad AA, Elawad MA: Prevalence of intestinal parasite infection in primary school children in Elengaz area, Khartoum, Sudan. Acad Res Int. 2014 Mar 1; 5(2): 86.\n\nSiddig HS, Mohammed IA, Mohammed MN, et al.: Prevalence of intestinal parasites among selected group of primary school children in Alhag Yousif Area, Khartoum, Sudan. Int J Med Res Health Sci. 2017 Jan 1; 6(8): 125–131.\n\nAbd Alla A: Parasitic Contamination Rate of Arachishypogaea L (Groundnuts), Citrulluslanatus Seeds (Watermelon Seeds), and Ziziphusspina-christi (Nabag) Sold by Street Venders in Khartoum State- Sudan. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "98828",
"date": "15 Nov 2021",
"name": "Samar Al Nahhas",
"expertise": [
"Reviewer Expertise parasitology",
"infectious diseases",
"molecular diagnosis",
"immuno diagnosis",
"microbiology",
"enteric parasites",
"leishmaniasis",
"malaria",
"toxoplasmosis",
"echinococcusis...."
],
"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 scientific article addresses the frequency of parasitic infections in some vegetative crops. It addresses an important topic concerning both human and animal nutrition. Raw vegetables and fruits are one of the most essential sources of nourishment. They often contribute to an epidemiological role in the transmission of parasitic food-borne diseases. Usually, fruits and vegetables become contaminated with different parasitic phases (cyst, oocyst, ova, and larvae) during irrigation by waste water or by direct contamination from animals and humans during harvesting, packing, transport processing, distribution, and marketing.\nIn Sudan as in many countries revealed the presence of different parasites species like soil worms, protozoa, fungus…etc. Identifying parasitic contamination will help fight these infections, because knowing contamination rates allows applying strict control of fruit and vegetable cultivation areas, such as keeping animals far from direct contact with agricultural crops, periodic inspection of water sources used in irrigation, as well taking the necessary preventive measures.\nI have some points that need to be clarified:\nThe authors record the Sellers ‘gender and age group, what is the benefit? Page 5: last paragraph before discussion, they mentioned “The 31-40 age group had the highest contamination rate …… outcome positivity”. Have the authors tested stool samples isolated from vendors?\n\nIt is not possible to distinguish and differentiate E. histolytica from the morphologically identical nonpathogenic species E. dispar and E. moshkovskii using light microscopy. How did the authors confirm the presence of Entamoeba histolytica?\n\nThe authors applied two techniques: FECT and sugar floatation. What is the benefit?\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": "7477",
"date": "29 Nov 2021",
"name": "Ahmed Abd Alla",
"role": "Author Response",
"response": "Here we need to know the effect of gender and age group in the transmission of parasites through the crops, although some crops are sold by females more than males, like tasali. We didn't take stool specimens, but of course, we mean by positive the crops are affected not the person. Yes, it's difficult to distinguish between the species by light microscope, so we change all E. histolytica to E. histolytica/E.dispar/E.moshkovskii. Here we want to compare which is the best."
}
]
},
{
"id": "98829",
"date": "19 Nov 2021",
"name": "Erastus Mulinge",
"expertise": [
"Reviewer Expertise Molecular epidemiology",
"Parasitology and One Health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript describes intestinal parasite contamination in food items sold by street vendors in Khartoum, Sudan. These parasitic agents detected are significant causes of diarrhea and other gastrointestinal symptoms which are major public health problems and therefore this manuscript deserves indexing.\nMajor issues\nThe conclusion seems to be a continuation of the results section. Please make conclusions based on these findings, like the implication of these findings to public health and possible control measures as well as what further studies could focus on.\n\nClarify the difference: the text (page 4) stated that 21 samples were positive for parasites by sugar flotation but in the table, it is 22.\nMinor issues\nReplace Entamoeba histolytica, address this as Entamoeba histolytica/E.dispar/E. moshkovskii throughout the manuscript.\n\nLook carefully throughout the manuscript and clear all the spacing mistakes.\n\nChange the last sentence in page 3 to G. lamblia, E. histolytica, A. lumbricoides, Trichuris trichiura, A. doudenale, N. americanus and S. stercoralis.\n\nAvoid the word \"then\" in the methods.\n\nShow p values for correlations in tables 2 and 3.\n\nResults: the last paragraph, \"The results revealed that E. histolytica was the dominant parasite across all city, with prevalence rates\" – change to \"all cities\".\n\nDiscussion: the previous study was 60% - do you mean the present study?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": [
{
"c_id": "7478",
"date": "29 Nov 2021",
"name": "Ahmed Abd Alla",
"role": "Author Response",
"response": "Major issues The conclusion seems to be a continuation of the results section. Please make conclusions based on these findings, like the implication of these findings to public health and possible control measures as well as what further studies could focus on. Author response: I added a paragraph in the conclusion section in response to this. Clarify the difference: the text (page 4) stated that 21 samples were positive for parasites by sugar flotation but in the table, it is 22. Author response: I revised my data and I found the table is right, so I changed it in text. Minor issues Replace Entamoeba histolytica, address this as Entamoeba histolytica/E.dispar/E. moshkovskii throughout the manuscript. Author response: I respond to these all throughout the text and I changed all E. histolytica with histolytica/E.dispar/E. moshkovskii. Look carefully throughout the manuscript and clear all the spacing mistakes. Author response: I respond to this. Change the last sentence in page 3 to G. lamblia, E. histolytica, A. lumbricoides, Trichuris trichiura, A. doudenale, N. americanus and S. stercoralis. Author response: I respond. Avoid the word \"then\" in the methods. Author response: I respond to this. Show p values for correlations in tables 2 and 3. Author response: l added p-value under Tables 2 and 3. Results: the last paragraph, \"The results revealed that E. histolytica was the dominant parasite across all city, with prevalence rates\" – change to \"all cities\". Author response: I changed it as the reviewer said. Discussion: the previous study was 60% - do you mean the present study? Author response: I changed 'previous' to 'present'. I hope I clarify all the things."
}
]
}
] | 1
|
https://f1000research.com/articles/10-586
|
https://f1000research.com/articles/11-64/v1
|
19 Jan 22
|
{
"type": "Research Article",
"title": "Anomalous energy consumption detection using a Naïve Bayes approach",
"authors": [
"Jia Yan Lim",
"Wooi-Nee Tan",
"Yi-Fei Tan",
"Jia Yan Lim",
"Wooi-Nee Tan"
],
"abstract": "Background: Industrial energy management has emerged as an important component in monitoring energy consumption particularly with the recent trend of migrating towards IR 4.0. The capability to detect anomalies is essential as it serves as a precautionary step for real-time response to mitigate the maximum demand penalty. The purpose of this research was to develop a high accuracy anomalies detection algorithm to identify anomalies in the energy consumption data recorded by a smart meter. Methods: The proposed algorithm utilized supervised and unsupervised machine learning techniques, namely Isolation Forest and Gaussian Naïve Bayes. The data were first labeled by using Isolation Forest to categorize them into normal and abnormal groups. This was followed by Gaussian Naïve Bayes to classify and predict the anomalies of the smart meter reading. Results: These machine learning techniques showed significant accuracy in predicting the anomalies in smart meter readings. The data used were simulated data collected in less than a month with 30-minute reading intervals. The data were divided into testing and validation sets according to a ratio of 7:3. The balanced accuracy score in predicting anomalies for each different smart meter was above 89%. The average precision, average recall and average F1 score for the normal data were 98%, 99% and 98%, respectively. Whereas the corresponding scores for the abnormal data set were 95%, 90% and 92%. Conclusions: The proposed algorithm is a hybrid approach based on Isolation Forest and Gaussian Naïve Bayes and it provided satisfactory accuracy in anomaly electricity consumption detection based on smart meter readings. The study presents a quick and simple method for categorizing energy consumption data as normal or abnormal, which assists in automatically labelling vast datasets of energy consumption readings. The proposed approach establishes a fundamental framework for predicting the occurrence of anomalies in the industrial energy management system.",
"keywords": [
"anomaly detection",
"energy consumption",
"data labeling",
"Isolation Forest",
"Gaussian Naïve Bayes",
"energy management",
"machine learning techniques"
],
"content": "Introduction\n\nPeople nowadays are continuously looking for new ways to utilize energy to improve their lives, therefore the demand for it is increasing. Most of the time, companies and industries struggle to monitor all their devices at the same time, which can lead to power wastage at any time. As a result, operational expenses will be greater than necessary. Besides that, power wastage contributes to global warming by releasing carbon when energy is generated through burning coal, gas, and oil. Hence, solutions are required to address these issues. Energy Management Information Systems (EMIS)1 or Building Energy Management Systems (BEMS)2 are the tools for continuous energy management monitoring that collect and analyze energy data on a regular basis. However, since no fixed characteristics can be retrieved, and no current static model of energy can be referred to, they give a low accuracy in predicting electricity consumption. According to an article published in Energy Malaysia,3 consumers may use the information supplied by smart meters to assist them to take prompt action in terms of power usage and waste. However, a model which is able to give early detection of deviations from historical energy usages is important and beneficial to multiple parties.\n\nMany authors have conducted research on detecting the abnormal behavior of power usage. Yassine Himeur et al.,4 used a rule-based model to extract micro-moment features. In their method, the accuracy varied from 93.91% to 99.58% depending on the types of datasets. The main limitation of their proposed work was related to the use of supervised learning in training the classifier. Wenqiang Cui and Hao Wang5 proposed a hybrid model that combines polynomial regression and Gaussian distribution to detect the anomalies of data. They focused on school power consumption and were able to detect anomalies with 0 false-negative and an average precision higher than 91%. However, the model must be trained manually. Ma and Zhang6 developed a method to detect abnormal building energy consumption in real time. They used fractal correlation dimension (FCD) and proper orthogonal decomposition linear stochastic estimation (POD-LSE). They claimed that the performance of the method depended on the threshold selected. Thus, improvement was required by integrating with other intelligent algorithms. Jecinta Mulongo et al.,7 used support vector machines (SVM), K-Nearest Neighbors (KNN), Logistic Regression (LR), and MultiLayer Perceptron (MLP) to detect anomalies in power generation plant data. They reported that MLP has the best performance in the evaluation measurement with a score of 96% in the K-fold cross validation test. In addition, deep learning has also received increasing interest for abnormality detection.8–10 Besides using machine learning and deep learning to detect anomaly electricity consumption, statistical techniques are used to monitor the consumption pattern. For example, Lin and Claridge11 used the deviation between collected and simulated energy usage and also the standard deviation of the residuals to detect the abnormal consumption. The limitation here was that only limited assumed cases were used. Araya et al.,12 used sliding window framework to capture contextual characteristics and historical sensor data in detecting the anomalous pattern. Liu et al.,13 proposed a statistical-based online detection technique with a Lambda scheme, which involved an in-memory distributed computing algorithm. Chen et al.14 also proposed a statistical predictive method utilizing mean and variance in detecting the energy anomalies.\n\nOne of the challenges that complicates the development of anomaly detection technique is the absence of labelled ground-truth datasets. There is a lack of research addressing how to classify energy consumption readings as normal or abnormal, as well as the nature of the abnormality.15 Additionally, as data on electricity consumption continues to expand tremendously, the properties of big data become more apparent, which further complicates the process of detecting anomalies. To that end, this paper proposes a method for detecting anomalies in energy consumption readings using an unsupervised approach that combines Isolation Forest and Naive Bayes models. The Isolation Forest is shown to be capable of detecting not only point anomalies with peaks, but also contextual anomalies. Whereas, when combined with Naive Bayes, the possibility of performing anomaly detection without retraining the data is demonstrated. This hybrid approach to labeling energy consumption readings demonstrates a straightforward and efficient method for assisting in the energy consumption readings labeling, which is critical in today's rapidly growing data volume era.\n\nIn this paper, a two-stage anomalous detection model is proposed to detect any anomalies of smart meter readings. This paper is organized as follows: Section 1 is the introduction, section 2 describes the methodology, which includes data labelling and the detection model. Section 3 presents the results and discussion. Finally, we conclude the research and introduce future work in Section 4.\n\n\nMethods\n\nThe anomalous detection model is built in two stages. The first stage focuses on utilizing the Isolation Forest in labeling the energy consumption data into two categories: normal consumption or abnormal peak. In the second stage, the energy consumption data as well as the corresponding labelled categories are then used to train a detection model using the Gaussian Naïve Bayes approach. The trained model can then be used to detect any anomalous unseen energy consumption data. The proposed model is implemented using the Python programming language, version 3.7 (RRID:SCR_008394).\n\nIsolation Forest is one of the unsupervised machine learning algorithms used to detect anomalies in a dataset. Unlike supervised machine learning algorithms, Isolation Forest does not require any label or classification for the data to be analyzed. The algorithm isolates or separates anomalies by considering anomalies as instances that are less likely to occur or attribute values that are very different from normally attributed values. For Isolation Forest, the anomaly score is calculated with the equation below:\n\nFigure 1 gives the labelling flow chart using Isolation Forest. The unlabeled data was first imported into the Jupyter Notebook (Jupyter Notebook, RRID:SCR_018315). The Isolation Forest from sklearn.ensemble was then used to identify the anomaly scores. In our work, the anomaly scores above 0.53 were classified as abnormal data. The classified values of C0=0 were used to indicate normal energy consumption while C1=1 indicated anomaly energy consumption.\n\nThe Gaussian Naïve Bayes is one of the most popular classifier algorithms in data mining and the data science field. It is well known since it is a simple technique for deciphering binary or categorical input values, and it does not necessitate a large amount of data for training. Since the energy consumption data is in a continuous form, the Gaussian Naïve Bayes that follows a Gaussian normal distribution was chosen to build the detection model. In general, Gaussian Naïve Bayes calculates the probability density of v for certain data to be assigned to respective classes according to the equation:\n\n\nResults\n\nThree smart meter readings were simulated in the analysis, namely smart meter ID A, smart meter ID B and smart meter ID C. The energy curves of each of these meter readings exhibited varied behavior and their respective energy consumption profiles are depicted in Figure 2. Most of the spikes in the energy curve of smart meter ID A are of similar height. However, the peak values of the energy curve in smart meter ID B are more variable. Meanwhile, the energy curve of smart meter ID C is flatter.\n\nTo ensure that the verification process was performed without bias, the data was categorized in a 70:30 ratio, with 70% of data utilized for training, and 30% of data reserved for verification as unseen data to the training model. The performance of the anomalous detection model was evaluated using the following formulae on precision, recall and F1 score:\n\nTP, FP and FN refer to true positive, false positive and false negative, respectively.\n\nTake the case when positive (P) refers to the anomalous point, for example, then TP denotes that the abnormal points are accurately identified as abnormal, whereas FP denotes that the normal points are incorrectly detected as abnormal by the model. Finally, abnormal points detected as normal by the model are referred to as FN. Therefore, the precision gives the proportion of detected anomalous points that are actually abnormal. The counterpart of precision is recall, which refers to the ability to recognize abnormal points among the actual abnormal points. F1 score combines precision and recall and calculates the harmonic mean. The F1 score reaches its optimum value of 1 if both precision and recall are both at 100%.\n\nTable 1 summarizes the above scores for smart meter ID A, smart meter ID B and smart meter ID C. The calculations were performed for two cases when the positive, P = 0 and when the positive, P = 1 .\n\nThe time series dataset involved is known to have issues of imbalanced data, with a large portion of the data considered normal consumption. The performance of the proposed model is further evaluated by balanced accuracy, a well-known metric for imbalanced data. The balanced accuracy is given as:\n\n\nDiscussion\n\nIn the performed simulation, labeling based on Isolation Forest was performed to the given time series data to identify the anomalous instances. The red dots associated with the peaks of the energy profiles in Figure 2 refer to the identified anomalous points. It can be observed that the Isolation Forest approach was able to detect almost all the local maximum points, which coincided with the instances of peaks in the energy consumption profiles. This tallied with the requirement of anomalous energy detection, as the spikes are not merely tied to the magnitude in kW, but mainly depend on the behavior of the profile in its neighborhood. Thereby, Isolation Forest is able to capture the peak regardless of the pattern exhibits in the dataset. Despite the fact that the peak’s value is low in comparison to the rest of the overall dataset, it is still an atypical peak when compared to surrounding past measurements that are lower. Based on the simulation results, we can observe that Isolation Forest is a suitable strategy for auto labeling the smart meter readings. The approach is relatively direct to implement when compared to alternative approaches that define or predict the anomalies based on absolute magnitude analysis with mean and variance.15 Isolation Forest is especially valuable if the user’s behavior changes with the seasons, such as when the energy readings are high during high production periods but low during low production periods. In summary, Isolation Forest is capable not only in detecting the point anomalies, but also in detecting the peak anomalies in contextual perspectives. However, if using Isolation Forest to classify anomalies requires processing an entire series of data in a specific window, this may not be feasible given the rapid growth of electricity consumption data. To that end, the Isolation Forest-labeled data is used to train a Naive Bayes model, which enables rapid classification of a single piece of data into normal or abnormal states without requiring previous points to be processed batch-wise as in Isolation Forest. For both classification results by Naïve Bayes model, the precision scores obtained for all smart meters were above 0.85, the recall values were above 0.79 and the F1 scores were above 0.88. The recall value of smart meter ID C for P = 1 was 0.79, which was the lowest score of all. This indicates that the model could only recognize 79% of the actual anomalous data, which could be related to the flattening trend of the energy consumption profiles, making it more difficult and challenging to identify spikes. In general, the performance of the anomalous detection models was satisfactory. The average F1 score was 0.98 and 0.92, for normal and abnormal data, respectively. This indicates that the model has harmonic high performance for both precision and recall. The time series dataset involved is known to have the issues of imbalanced data, with a large portion of the data considered normal consumptions. The balanced accuracy score for all smart meters was above 0.8947. Therefore, the proposed anomalous detection model not only detects the anomalous points successfully, but also classifies the normal points appropriately.\n\n\nConclusions\n\nThis paper proposed a two-stage anomalous detection model, combining the Isolation Forest and Gaussian Naïve Bayes. The performed simulations showed that a balanced accuracy score of at least 0.8947 was achieved. The Isolation Forest approach was used to label normal and abnormal data, and it successfully identified the abnormal spikes based on the behavior of the energy consumption pattern rather than just the magnitude of consumption. In detecting anomalies, the Gaussian Naïve Bayes gave a satisfactory performance in detecting the abnormal points as well as the normal points. The proposed approach combining Isolation Forest and Naive Bayes can be used to detect anomalies in a given time series of energy consumption. In comparison to using only the Isolation Forest for classification, this hybrid approach provides a straightforward method for labelling the data, which is particularly useful when the data set is large and arrives in batches. Classification does not have to be repeated using Isolation Forest and all available data; rather, once trained, the trained Naive Bayes model can classify effectively. However, the size of the current simulation was limited by the available dataset. A larger amount of data should be collected and applied to this model in the future. Furthermore, the optimum dataset size to achieve high accuracy also needs to be identified.\n\n\nData availability\n\nOpen Science Framework. Underlying data for ‘Anomalous energy consumption detection using a Naïve Bayes approach’, https://doi.org/10.17605/OSF.IO/CKTQS17\n\nThis project contains the following underlying data:\n\n• Smart meter data.xlsx\n\n\nSoftware availability\n\nArchived source code at time of publication: https://doi.org/10.17605/OSF.IO/CKTQS17\n\nThis project contains the following parameter code:\n\n• Model A GNB.ipynb\n\n• Model B GNB.ipynb\n\n• Model C GNB.ipynb\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC BY 4.0 Public domain dedication)",
"appendix": "References\n\nHorinov S, Horinova S: Energy management systems. GCSEEA Global Conference on Sustainable Environment, Energy and Agriculture (GCSEEA-2017). 2017. Publisher Full Text\n\nShapi MKM, Ramli NA, Awalin LJ: Energy consumption prediction by using machine learning for smart building: Case study in Malaysia. Developments in the Built Environment. 2021; 5: 100037. Publisher Full Text\n\nRamli H, Ahmad SS, Abdullah A, et al.: Let's Get Smart. Energy Malaysia, Energy Commission Malaysia. 2019; 19: 8–15.\n\nHimeur Y, Alsalemi A, Bensaali F, et al.: A novel approach for detecting anomalous energy consumption based on micro-moments and deep neural networks. Cogn. Comput. 2021; 1–23.\n\nCui W, Wang H: Anomaly detection and visualization of school electricity consumption data. 2017 IEEE 2nd International Conference on Big Data Analysis (ICBDA). 2017; pp. 606–611. Publisher Full Text\n\nMa Z, Song J, Zhang J: A real-time detection method of abnormal building energy consumption data coupled POD-LSE and FCD. Procedia Eng. 2017; 205: 1657–1664. Publisher Full Text\n\nMulongo J, Marcellin A, Theophilus A-S, et al.: Anomaly Detection in Power Generation Plants Using Machine Learning and Neural Networks. Appl. Artif. Intell. 2020; 34(1): 64–79. Publisher Full Text\n\nManimaran A, Chandramohan D, Shrinivas S, et al.: A comprehensive novel model for network speech anomaly detection system using deep learning approach. Int. J. Speech Technol. 2020; 23: 305–313. Publisher Full Text\n\nAldweesh A, Derhab A, Emam AZ: Deep learning approaches for anomaly-based intrusion detection systems: A survey, taxonomy, and open issues. Knowl.-Based Syst. 2020; 189: 105124. Publisher Full Text\n\nChalapathy R, Chawla S: Deep learning for anomaly detection: A survey. arXiv:1901.03407. 2019.\n\nLin G, Claridge D: A temperature-based approach to detect abnormal building energy consumption. Energ. Buildings. 2015; 93: 110–118. Publisher Full Text\n\nAraya DB, Grolinger K, ElYamany HF, et al.: Collective contextual anomaly detection framework for smart buildings. 2016 International Joint Conference on Neural Networks (IJCNN). 2016; pp. 511–518. Publisher Full Text\n\nLiu X, Iftikhar N, Nielsen PS, et al.: Online anomaly energy consumption detection using lambda architecture. International Conference on Big Data Analytics and Knowledge Discovery. Porto: Springer; 2016; pp. 193–209.\n\nChen B, Sinn M, Ploennigs J, et al.: Statistical Anomaly Detection in Mean and Variation of Energy Consumption. 2014 22nd International Conference on Pattern Recognition. 2014; pp. 3570–3575. Publisher Full Text\n\nHimeur Y, Alsalemi A, Bensaali F, et al.: A Novel Approach for Detecting Anomalous Energy Consumption Based on Micro-Moments and Deep Neural Networks. Cogn. Comput. 2020; 12: 1381–1401. Publisher Full Text\n\nLiu FT, Ting KM, Zhou Z: Isolation Forest. 2008 Eighth IEEE International Conference on Data Mining. 2008; pp. 413–422. Publisher Full Text\n\nLim JY, Tan W-N, Tan Y-F: Anomalous energy consumption detection using a Naïve Bayes approach. Data and ipynb files. Open Science Framework. 2021. Publisher Full Text"
}
|
[
{
"id": "120393",
"date": "16 Feb 2022",
"name": "Kim Gaik Tay",
"expertise": [
"Reviewer Expertise Machine learning"
],
"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 demonstrates the use of unsupervised machine learning techniques by Isolation Forest to label normal and anomalous points of energy consumption, as well as a Gaussian supervised method, namely Naïve Bayes, to classify the normal and anomalous points of energy consumption and predict the unseen anomalies from the smart meter reading. This work could be approved pending several polishes.\nMethods section of Abstract. Please change “The proposed algorithm utilized supervised and unsupervised machine learning techniques, namely Isolation Forest and Gaussian Naïve Bayes” to “The proposed algorithm utilized unsupervised and supervised machine learning techniques, namely Isolation Forest and Gaussian Naïve Bayes.” Because Isolation Forest is unsupervised while Naïve Bayes is supervised method.\n\nIn Results section of Abstract, “The data used were simulated data collected in less than a month with 30-minute reading intervals. The data were divided into testing and validation sets according to a ratio of 7:3.” Is the data here training data? The training data was divided into 70% training and 30% testing?\n\nThe statement before Results section states that “The proposed anomalous detection model was verified using simulated smart meter readings with each reading for a smart meter collected in 30-minute intervals for a period of 576 hours. Firstly, the pattern of the electricity data of the Irish Social Science Data Archive (ISSDA) were investigated. Next, three sets of smart readings were generated based on different values of peak to-peak and valley-to-valley intervals. Then, the energy consumption values were manually created based on assumption of different users’ behavior.” Please clearly explain the training, testing and validation datasets and their ratio. Are training datasets from ISSDA and testing datasets generated manually? Are the 30-minutes intervals for a period of 576 hours testing data or training data? How is data generated based on peak to peak and valley-to-valley intervals? The abstract mentioned validation, but here no: please tally this section with the abstract.\n\nExplain in greater detail how Isolation Forest can label energy distribution as normal or anomalous? Also, how does one calculate h(x) from x? What is n, s(x,n)? The equation to calculate anomaly score should labeled as (1).\n\nExplain each term in Examples (1) and (2) such as p(x=ν|Ck), p(C1|x), p(x|C1), p(C1), p(x). How to calculate ν,p(x|C1), p(C1), p(x)? Explain further what Bessel corrected variance is. What is the usage of Example (1) in classifying if a point is normal or abnormal?\n\nIs Figure 2 training, validation or testing results? Where is normal point?\n\nSince you define precision as TP/(TP+FP), and recall as TP/(TP+FN), then it is confusing for the reader that in Table 1, in the section for Normal (when P = 0) that you use the labels Precision and Recall here as well. I would recommend writing Abnormal Precision as = TP/(TP+FP ) and Normal Precision as TN/(TN + FN); Abnormal Recall as TP/(TP+FN ) and Normal Recall as TN/(TN + FP); and Abnormal F1 score = 2. abnormal precision* abnormal recall/ (abnormal precision + abnormal recall) and normal F1 score = 2. normal precision* normal recall/ (normal precision + normal recall).\n\nWhat are P and N in balanced accuracy?\n\nFrom Discussion part, line 7, “… it is still an “atypical” peak…” Any typo at “atypical”?\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": "177529",
"date": "15 Jun 2023",
"name": "Yassine Himeur",
"expertise": [
"Reviewer Expertise Anomaly detection",
"Building Energy Management",
"AI/ML/DL"
],
"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 research aimed to create an accurate anomaly detection algorithm for industrial energy consumption, leveraging IR 4.0 trends. The algorithm uses a hybrid approach of Isolation Forest and Gaussian Naïve Bayes machine learning techniques, categorizing smart meter readings into normal and abnormal groups. The method showed over 89% accuracy in simulated testing, promising fast, automatic labeling of energy data to predict and manage anomalies, aiding in industrial energy management.\nThe motivation of introducing this study is not clear. Please improve this part by highlighting the research gap of existing works.\n\nThe main contribution of this article must be well presented. Please summarize them as bullet points.\n\nThe literature review of this article is very terse. Many recent anomaly detection of energy consumption articles have been missed in the Introduction. The authors should discuss the following articles before introducing their method: A dynamic anomaly detection method of building energy consumption based on data mining technology1; Artificial intelligence based anomaly detection of energy consumption in buildings: A review, current trends and new perspectives2; Anomaly detection based on joint spatio-temporal learning for building electricity consumption3; Smart power consumption abnormality detection in buildings using micromoments and improved K‐nearest neighbors4; An innovative deep anomaly detection of building energy consumption using energy time-series images5; Exploring Deep Time-Series Imaging for Anomaly Detection of Building Energy Consumption6; Detection of appliance-level abnormal energy consumption in buildings using autoencoders and micro-moments7; LSTM-Markov based efficient anomaly detection algorithm for IoT environment8; A Two-Stage Energy Anomaly Detection for Edge-based Building Internet of Things (BIoT) Applications9; SUSAN: A Deep Learning based anomaly detection framework for sustainable industry10\nThe authors have the opportunity to leverage these references to compile an extensive literature review. By\n\n(i) examining the strengths and weaknesses of each source, they can pinpoint the research gap and bolster the justification for their proposed method; and\n\n(ii) incorporating a comparative table to analyze the research within these references—from the models and datasets utilized to their applications, environments, advantages, and limitations—would provide a comprehensive overview.\n\nCollectively, these measures will enhance the literature review section and significantly strengthen the overall quality of the paper.\n\nReferences 4 and 15 are repeated. Please correct\n\nThe limitations of the proposed method should highlighted in the conclusion before deriving future work.\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/11-64
|
https://f1000research.com/articles/11-63/v1
|
19 Jan 22
|
{
"type": "Research Article",
"title": "Comparisons of the effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents: a case of oxalic acid and succinic acid",
"authors": [
"Onyeocha V. O.",
"Onuchukwu A. I.",
"Enemo R. E.",
"Onuchukwu A. I.",
"Enemo R. E."
],
"abstract": "Background: The molecular distributions of solutes in binary immiscible solvents as used in partition coefficient technique serve as measures of the solute separation, concentration and beneficiation from contaminants. Methods: The effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents were investigated at 300C and atmospheric pressure. The activities from the interactions with changes of concentrations within the solvents were analysed. These were done using simple titration method. The solutes were distributed in the binary solvents and the concentrations from the two layers formed were determined by titration method. The interactions of oxalic acid and succinic acid in carbon tetrachloride-water, diethyl ether-water, and n-hexane-water were studied for the partition coefficient values in the respective systems, to determine the nature and degree of the interfering reactions that are affecting the distributions, and to ascertain the best binary solvents from the three systems. Results: Oxalic acid has the partition coefficient of 0.0738 in carbon tetrachloride-water with the dimerization constant of -15.7092 and ionization constant of 0.0303. Oxalic acid has the distribution coefficient of 0.0173, dimerization constant of 144.0167 and the ionization constant of 0.0035 in diethyl ether-water. Oxalic acid has the partition coefficient of 0.0279, dimerization constant of 20.2798 and ionization constant of 0.0019 in n-hexane-water. Succinic acid has the partition coefficient of -0.05617, dimerization constant of -18.5655 and ionization constant of 0.0284 in carbon tetrachloride-water. In diethyl ether-water, succinic acid has the partition coefficient of 0.0427, dimerization constant of -18.1611 and ionization constant of 0.0332. In n-hexane-water, succinic acid has the partition coefficient of -0.04274, dimerization constant of 71.9491 and ionization constant of 0.0265. Conclusion: From these results, carbon tetrachloride-water is recommended for the purification and extraction of oxalic acid from contaminants. Carbon tetrachloride-water is also the best binary immiscible solvent for succinic acid.",
"keywords": [
"Partition Coefficient",
"Binary Solvent",
"Oxalic Acid",
"Succinic Acid",
"Dimerization",
"Ionization"
],
"content": "Introduction\n\nWhen a solute is put in a binary solvent system, the solute circulates itself within the two solvents, until equilibrium is reached, in agreement with Nernst’s distribution law.1 The ratio of the concentrations of the solute in the two layers of the solvents is constant, at any temperature.2,3 This principle applies on the condition that the solute does not undergo association, or is involved in chemical processes in any of the solvents.3,4 This partition law is defined by the relation:\n\nwhere\n\nCXA is the total amount of the species (X) in moles per litre in the layer A; CX∗B is the total amount of the species (X) in moles per litre in the layer B that was not used in any chemical processes; kD is the parti,tion coefficient; m and n are the stoichiometric coefficients of the products of the dimerization, ionization, or any reaction process happening in solvent A; K is the dimerization constant (or the reaction constant); and x defines the stoichiometric coefficient of the solute (X) in the solvent.\n\nThe constant kD shows the degree of the solubility/dissolution of the solute in the two solvents, A and B, at the temperature studied. The temperature (T), pH of the solution, and any chemical reaction of the solute with any of the solvents all influence the partition coefficient, kD (Britannica).2,5 kD is a fundamental measurable factor that defines the degree of solute recovery in solvent extraction.2,5 The value of kD depends on the relative solubility of a substance in two-immiscible solvents as expressed by equation (1). The immiscible solvents are chosen based on the physical nature as well as the chemical characteristics of the substance in the binary immiscible solvents.2,7 The solute when introduced into binary immiscible solvents disperses into the two solvents; when equilibrium reaches, the substance distributes its molecules between the two solvents in line with the Nernst’s distribution law. The ratio of the dissolution of this solute in the binary immiscible solvents is constant at any temperature.3,8\n\nConsider the equation,\n\nIn equation (5), the solute, X (for example succinic acid or oxalic acid), disperses into the solvent, A, with the involvement of a chemical reaction to form the products M and N.\n\nWhen dissociation of the solute X takes place in the solvent A,\n\nSo,\n\nWhen association of the solute takes place in the solvent,\n\nThis partition coefficient, kD, gives the measure of the dispersion of the solute in the binary solvent, A and B at a defined temperature. The temperature (T) of the system and the chemical reaction of the solute with one or both of the solvents influence the partition coefficient, kD.3,9\n\nOrganic compounds such as succinic acid, carbon tetrachloride, acetic acid, oxalic acid, n-hexane, associate to form dimers, and polymers.10,11 Molecules like succinic acid and oxalic acid ionize in an aqueous solution, forming the conjugate anions as shown in scheme I and II below.\n\nScheme I: Dissociation/ionization of oxalic acid in aqueous solution\n\nOxalic acid (HOOCCOOH) ionizes in water to form the oxalate, as shown below:\n\nThe stability of the dimer of oxalic acid has a minimum energy structure that is stabilized by two intermolecular and four intramolecular hydrogen bonds. The most stable structure in previous studies is supported by two intermolecular, and three intramolecular hydrogen bonds.12\n\nScheme II: Dissociation/ionization of succinic acid\n\nSuccinic acid is a dicarboxylic acid also, (HOOCCH2CH2COOH).\n\nSuccinic acid could undergo two successive reactions as a diprotic acid.10\n\nThus,\n\nSuccinic acid is fairly soluble in water, and sparingly soluble in ether. On heating succinic acid, a large amount sublimes and the remainder is converted into the cyclic anhydride (succinic anhydride). Succinic acid also gives anhydrides in organic solvents at low temperatures. This is shown below in scheme III.\n\nScheme III: The succinic anhydride formation of succinic acid.\n\nThe degree of the dissolution of non-ionic compounds like succinic acid and oxalic acid is dependent on their polarity. Non-polar compounds dissolve in non-polar solvents while highly polar compounds dissolve in highly polar solvents. A carbon tetrachloride molecule is balanced ionically, while water molecules are involved in the strong hydrogen bonding. Carbon tetrachloride is a non-polar solvent, and water is a polar solvent. Carbon tetrachloride is insoluble in water, this is due to the fact that water molecules are bonded to each other by strong dipole-dipole bonds (hydrogen bonding).11,13 There are weak attractive forces between water molecules and carbon tetrachloride molecules.10,14 Carbon tetrachloride is immiscible with water.\n\nThe formation of dimers, anhydrides, and ions in the binary immiscible solvents affects the distribution of solutes in the binary immiscible solvents. A high dimerization constant (association constant), K, or ionization constant,α, results in a small value of the partition coefficient, and less efficiency of partition coefficient technique, in solvent extraction as depicted in the equation:\n\nMany compounds and substances such as oxalic acid, acetic acid, ethylenediaminetetraacetic acid and succinic acid can exist in the form of dimers or anhydrides in non-hydrogen bonding liquids.10,14 Most compounds like oxalic acid and succinic acid are crystals in their pure state. This discussion focuses on a compound with lattice structure. When the crystal is introduced into the solvent, the forces that hold the crystal units together are weakened; consequently, the units are liberated for solvation and mobility.15 According to Onuchukwu,15 ions in a solution devoid of any electric field are known to indulge in identical random movement characterized by random swimming in the solution.\n\nThe degrees of the dissolution of non-ionic compounds are influenced by their polarity. These non-ionic compounds are soluble in non-ionic solvents while polar substances dissolve in polar solvents. A non-polar compound like carbon tetrachloride is not soluble in water, a polar solvent. This is due to the fact that water molecules (H2O) cling to one another by the strong hydrogen bonding that exists between the oxygen and hydrogen atoms of the water molecule.2,11,13 Considering the nature of the bonding between water molecules (H2O) and carbon tetrachloride molecules (CCl4), it is viewed that there are weak van der Waal forces between the molecules of water and the molecules of carbon tetrachloride.16,17 Hexane is a non-polar solvent [www.sciencedirect.com]. It forms a binary immiscible solvent with water. The interaction of solutes with solvents could give rise to changes that result in the dissolution of the solute in the solvents. With succinic acid, the crystal packing of the molecules dislodges, and the molecules are separated from one another. The spaces between the molecules are filled in with the solvent molecules.14 This explanation defines solvation.18 When the mixture is made up of a homogeneous phase where the constituents cannot be separated from one another by a physical means, a solution is formed. The solvent is present in large excess quantity over the solute. Factors such as temperature, the nature of the solute, and the type of solvent are important in contributing to the dissolution of substances in solvents.2,19\n\nThe ion-solvent interaction is anchored on an ion with its neighboring water molecules. The ion is related to its environment. Given an ion of interest such as the oxalate (C2O2−4), surrounded by water molecules and ions, further increase in ionic concentration drives the water molecule to the property of ion-solvent attainment after the ion attract each other. This gives rise to an ion-ion interaction. The ion perceives not only solvent dipoles but also other ions. The mutual interactions between and amongst these ions constitute an essential part of the entire picture of ion–ion interaction which defines electrolytic solution. This ion-ion interaction determines the equilibrium properties of electrolytes and, effects the drift of ions.15,19\n\nThe constitution of the phase(s) of a solution is changeable, within a limit. A binary solution is made up of two solvents; a ternary solution is made up of three solvents. These solvents are immiscible, or partially miscible. The degree of the miscibility of the solvents is a continuum. The basic measurable factors for the state of the solution are temperature, pressure and concentration.2,18 Concentration shows the relative amounts of the solute, in moles per litre, of the solvent.\n\nWhen oxalic acid crystals as a solute are shaken up in a mixture of water and carbon tetrachloride as immiscible solvents, for example, it is found that the oxalic acid molecules distribute themselves between the water and carbon tetrachloride layers in such a way that at equilibrium, the ratio of the concentration of oxalic acid in these two phases is constant at any temperature studied.2,8 This observation is direct evidence of the solute-solvent interaction in accordance with attainment of thermodynamic equilibrium as defined in the ratio of solution of the binary immiscible solvent in the equation below.2,11,19\n\nEquation 16 is the mathematical expression of Nernst distribution law, which states that a substance distributes itself between two solvents until at equilibrium, where the ratio of the activities of the substance in the two phases remains constant at the given temperature and pressure. Additionally, if the concentrations of the solute in the two phases are expressed and designated by concentrations C, then equation (1) holds.2,17\n\nThe constant kD is called the partition coefficient of the solute between the two solvents.19,20 The magnitude of kD depends on the nature of the solute and the liquids involved, and the temperature (LibreTexts). The law is valid provided the solute does not undergo any chemical reactions such as association or dissociation in any of the two immiscible solvents.2,3 Also, the law does not apply to the total concentrations in the two phases. This partition coefficient, kD, measures the miscibility of the solute in the binary immiscible solvent formed by liquid A and liquid B, at any temperature. The temperature (T) of the solution and any chemical reaction of the solute in the solvents affect it..2,3\n\nWhen dimerization of the solute (X) occurs in one of the liquids, the dimerization reaction is represented as:\n\nThe equilibrium constant,\n\nUsing equations (2), (3), and (4),\n\nA plot of CXACX∗BvsCX∗B is a straight line with intercept kD and a slope that is equal to 2kD2K. This will enable the calculation of dimerization constant, K.\n\nWhen ionization of the solute (X) occurs in one of the liquids, the ionization reaction is represented as:\n\nThe ionization constant, α, is given by:\n\nUsing equations (2), (3), and (4),\n\nA plot of CXACX∗Bvs1CX∗B12 will give a straight line.\n\nWhen both dimerization and ionization reactions are taking place in solvents A and B respectively, then equation (2), (3), and (4) above are written as3:\n\nWhen a solution or mixture is put in a separatory funnel and shaken with an immiscible solvent, the solutes distribute in part, into the two phases.26 At equilibrium, the quantitative relation between the amounts of solute in the two phases is constant, and this is shown by the magnitude, kD, called the distribution coefficient/partition coefficient (LibreTexts). This technique was applied in the separation of morphine in ethyl acetate-water. When equal volumes of organic and aqueous layers are used, the partition coefficient, kD, gives the ratio of particles in each layer. The kD of morphine was reported to be 6. This shows that there will be six times as many morphine molecules in the solvent A phase as there are in the solvent B phase. The partition coefficient expresses the miscibility of the compound in the organic and aqueous phases. It is dependent on the solvents system used. Morphine has a kD of 2 in petroleum ether-water, and a kD of 0.33 in diethyl ether-water.\n\nGenerally, when the kD is less than 1 (kD <1), the compound distributes into the aqueous phase more than the organic phase.23 When kD = 1, the solute separates equally in the two phases that are involved, and it could be removed completely from the mixture. This applies when the bulk contaminant where the solute is seized is different from the two liquids that are used to form the binary solvent. This condition has been used in the solvent extraction of gold from alkaline cyanide solution by tetradecylmethylbenzylammonium chloride.24 For all cases, when kD > 1, complete separation of the solute from the contaminant can be done in many times.\n\nThe Partition coefficient technique has been applied in finding the ‘effective partition coefficient’ (kD) for silicon impurities.23 As reported, the process uses the impurities solubility difference in solid and liquid silicon called effective partition coefficient (kD). The measured impurities profiles in silicon are compared with the theoretically calculated impurities profiles to determine the effective partition coefficient. In studying the solidification process, the kD technique is applied for the determination of the silicon impurities.\n\nAccording to Kodolikar and Bhatkhande,25 solvent extraction is an important separation technique in chemical industrial separation and recovery. Thus, selectivity is defined as the ability of a solvent to extract one component of the mixture that contains more than one component, in preference to the other component(s), and partition coefficient shows the measure of the relative selectivity of components for each other.25 Selection of a solvent is considered the main factor in the making of a successful solvent extraction process, as it invariably determines the separation efficiency. The equilibrium data generated relates to selectivity and partition coefficient, for each individual constituent in the system.25 The concept used by Kodolikar and Bhatkhande25 proposes distribution coefficients calculation. Solvent extraction technology is used for the purification and concentration of organic substances, for both energy savings and for environmental protection (Britannica). The miscibility of oxalic acid with water at 303.15K is low. The miscibility is 12% in mass fraction of anhydrous oxalic acid and gives a dilute solution. This shows that the solvent extraction process is necessary for the removal of oxalic acid from wastewaters.26 The phenomenon of the partition coefficient is a direct consequence of the laws of thermodynamics. The driving force, which is defined in the partition coefficient (kD) values, shows the efficiency of the application of this principle in solvent extraction, in beneficiation of minerals. The value of kD depends on the relative solubility of the solute in the two immiscible solvents. When the partition coefficient, kD > 1, total extraction of the solute is made as many times as possible. Also when kD< 1, the compound partitions into the aqueous layer more than it distributes into the organic layer (LibreTexts).\n\nSolvent extraction is an important method of beneficiation of minerals (Study). Also log kD (partition coefficient) was used in drug recovery, beneficiation, and development.24 Body cells are likened to mechanical filters which are used to create two partitions like in solvent extraction in the use of organic solvent and aqueous solvent. Partition coefficient describes the relative solubilities of a solute in binary immiscible solvent. In drug development, body cells are likened to mechanical filters which could give the relative sizes of the material used for the development. This process is similar to solvent extraction with two immiscible solvents. Partition coefficient technique is used in research and development.\n\nAmong the minerals, compounds, and substances nature blessed mankind with are oxalic acid and succinic acid. The continued use and recycling of these compounds to their pure states necessitates that research determines the efficient method for the purification, beneficiation, and analyses of these compounds. Partition coefficient technique gives good separation effect, as it has a high degree of selectivity and fast mass transfer. It also has low energy consumption, large production capacity, fast action, easy continuous operation and ease of automation.29\n\nThe results from this research are shown in Tables 1 – 20 and Figures 1 – 18 below.\n\n\nMethods\n\nThe materials for the experiment are AnalaR Grade reagents27 of oxalic acid, succinic acid, carbon tetrachloride, diethyl ether, n-hexane, phenolphthalein, 0.5 M sodium hydroxide, and distilled water. A Drawell digital precision balance, model FA1204, and origin 50 software were used for the measurement of reagents and the creation of graphs, respectively. The various solutions of the binary immiscible solvents were prepared to get the stock solutions as described below.3,26 This method was used in the analyses of acetic and succinic acids in binary immiscible solvents, as described by Veronica et al.1 All measurements were done at 30°C and atmospheric pressure.\n\n20 g of sodium hydroxide solid was weighed into 500ml of distilled water in a conical flask. The mixture was shaken well by hand for complete dissolution of the solute. The mixture was then made up to 1000 ml (1litre) mark with more distilled water, in the conical flask.\n\n0.5 g of phenolphthalein solid was measured into 50 ml of 90% ethanol. The mixture was shaken vigorously by hand until the phenolphthalein dissolved completely. 50 ml of distilled water was then poured into the solution to ensure proper dissolution of the mixture. This solution gives the phenolphthalein solution (the indicator) for titrations.\n\n25.00 ml of distilled water was measured using a clean measuring cylinder into a separating funnel. 25.00 ml of carbon tetrachloride was measured using another clean measuring cylinder, and was poured into the same separating funnel with the water. The mixture was shaken well. This mixture forms the binary immiscible solvent.\n\n0.40 g of oxalic acid was measured out using a weighing balance. It was weighed into a binary immiscible solvent system of 25.00 ml of water and 25.00 ml of carbon tetrachloride in a separating funnel. The separating funnel was shaken up for 15-20 minutes by hand, for proper mixing of the content. The system was then allowed to stand for 60 minutes, until equilibrium was reached and separation of the organic and aqueous layer achieved. The lower organic layer was separated by hand, by pouring it gradually into a clean beaker while the upper aqueous layer was separated (decanted) into another clean beaker. These steps were repeated for 0.60 g, 0.80 g, and 1.0 g of oxalic acid to create four systems.\n\n10.00 ml of the organic phase of the 0.4 g system was titrated with 0.5 mol sodium hydroxide per 1 litre of water, with phenolphthalein as the indicator. The titration was carried out until a pink colour was obtained as the end point was reached. The volume of sodium hydroxide used was recorded. 10.00 ml of the aqueous phase was also titrated with 0.5 mol sodium hydroxide per 1 litre of water, again using phenolphthalein as an indicator until the end point was reached. Again, the volume of sodium hydroxide used was recorded. The experiment was repeated separately for the 0.60 g, 0.80 g, and 1.0g systems of oxalic acid. The concentrations of oxalic acid in the two phases were calculated.\n\nThe method for preparation of immiscible solvents I (method I) was exactly repeated using diethyl ether and water instead of carbon tetrachloride and water, with 0.40 g, 0.60 g, 0.80 g, and 1.0 g of oxalic acid respectively. The concentrations of oxalic acid in the two layers were also calculated.\n\nThe method for preparation of immiscibly solvents I (method I) was exactly repeated using n-hexane and water instead of carbon tetrachloride and water, with 0.40 g, 0.60 g, 0.80 g, and 1.0 g of oxalic acid respectively. The concentrations of oxalic acid in the two layers were also calculated.\n\n25.00 ml of distilled water was measured using a clean measuring cylinder, and poured into a separating funnel. 25.00 ml of carbon tetrachloride was measured using another clean measuring cylinder and poured into the same separating funnel above. The mixture in the separating funnel was shaken well. This mixture forms the binary immiscible solvent.\n\n0.40 g of succinic acid was measured out using the weighing balance. It was introduced into binary immiscible solvent system of 25.00 ml of water and 25.00 ml of carbon tetrachloride in the separatory funnel. The system was shaken vigorously for 15-20 minutes by hand. It was then allowed to stand for 60 minutes until equilibrium was reached and the separation of the organic and aqueous layers was achieved. The lower organic layer was decanted into a clean beaker while the upper aqueous layer was discharged into another clean beaker. All the activities here were done manually. These steps were repeated for 0.60 g, 0.80 g, and 1.0 g of succinic acid to create four systems.\n\n10.00 ml of the organic phase of the 0.4 g system was titrated with 0.5 mol sodium hydroxide per 1 litre of water, with phenolphthalein as the indicator. The titration was carried out until a pink colour was obtained as the end point was reached. The volume of sodium hydroxide used was recorded. 10.00 ml of the aqueous phase was also titrated with 0.5 mol sodium hydroxide per 1 litre of water, again using phenolphthalein as an indicator until the end point was reached. Again, the volume of sodium hydroxide used was recorded. The experiment was repeated separately for the 0.60 g, 0.80 g, and 1.0 g systems of succinic acid. The concentrations of succinic acid in the two phases were calculated.\n\nMethod II above was exactly repeated using diethyl ether and water instead of carbon tetrachloride and water, with 0.40 g, 0.60 g, 0.80 g, and 1.0 g of succinic acid respectively. The concentrations of oxalic acid in the two layers were also calculated.\n\nMethod II was also repeated using n-hexane and water instead of carbon tetrachloride and water, with 0.40 g, 0.60 g, 0.80 g, and 1.0 g of succinic acid respectively. The concentrations of oxalic acid in the two layers were also calculated.\n\nMethods I and II were used to determine the partition coefficients of the acids in the binary immiscible solvents. Every system of each binary solvent has two phases, aqueous and organic, which were separated manually by pouring each partition gradually into a beaker. The partition coefficient is given by “concentration of the acid in the organic layer (layer A) / concentration of the acid in the aqueous layer (layer B)”. Taking the case of oxalic acid in n-hexane-water system, the partition coefficient is given as, “concentration of oxalic acid in n-hexane/concentration of oxalic acid in water”.\n\nThe equation:\n\nThe reaction of oxalic acid with NaOH gives:\n\nthe concentration of the base, CB = 0.5 M\n\nThe volume of the acid (oxalic acid) = VA = 10 ml\n\nThe concentration of acid, CA, was calculated.\n\n\nResults and discussion\n\nThe values of the partition coefficient (kD) for oxalic acid in carbon tetrachloride-water at 30°C and atmospheric pressure were calculated as shown in Table 1.\n\nTable 1 shows the dissolution of oxalic acid in carbon tetrachloride and in water, and the degree of its subsequent extraction. The partition coefficient values show that the complete extraction of oxalic acid in this system could be done in many steps, and that oxalic acid dissolves more in water than in carbon tetrachloride. As the concentration of oxalic acid increases in water, the partition coefficient value decreases. In a situation where the contaminant is a material that is different from both water and carbon tetrachloride, the carbon tetrachloride-water system is also used to extract the oxalic acid from such contaminant.\n\nIntercept, kD = 0.07383\n\nslope = −0.17123, = 2kD2K, K = −15.7092\n\nK is the constant for the formation of oxalic acid dimers in carbon tetrachloride.\n\nThe magnitude of K is greater than that of kD. Also, the higher the magnitude of K, the more the formation of oxalic acid dimers.\n\nOxalic acid ionizes in water to form the oxalate, as shown in equations (9) and (10).\n\nThis table shows how the partition coefficient values relate with the concentration of oxalic acid in water. As the concentration of oxalic acid decreases, the partition coefficient value decreases too.\n\nFrom Figure 2, kD = −0.05098\n\nslope = 0.03931 = (KkD)1/2\n\nK = 0.0303 = α\n\nα is the reaction equilibrium constant represented in the ionization process. It gives the degree of the ionization of oxalic acid in water in the carbon tetrachloride-water system.\n\nBoth dimerization and ionization reactions are considered with oxalic acid in the two liquids, carbon tetrachloride and water respectively.\n\nEquation (23) is used.\n\nA plot of kD(1−α) vs CX*B(1−α) will give a straight line, α is the degree of ionization of oxalic acid in water\n\nThus, 1−α= 0.9697\n\nThis table presents the effect of ionization on the partition coefficient of oxalic acid in carbon tetrachloride-water. It also shows the effect of ionization on the concentration of oxalic acid in water. The concentration of oxalic acid in water increases linearly, while the partition coefficient value decreases in a similar manner.\n\nkD = 0.07165\n\nslope = −0.17144 = 2kD2K = 0.010267445K\n\nK = −16.6974\n\nK is the combined reaction equilibrium constant which is represented here in dimerization and ionization processes of oxalic acid in carbon tetrachloride-water system.\n\nThe values of the partition coefficient (kD) for oxalic acid in diethyl ether-water at 30°C and atmospheric pressure were calculated as shown in Table 4.\n\nTable 4 shows the dissolution of oxalic acid in diethyl ether and in water. The partition coefficient values show a gradual increase as the concentration of oxalic acid in the system increases. Oxalic acid dissolves more in water than in diethyl ether.\n\nIntercept, kD = 0.0173\n\nslope = 2kD2K = 0.08641\n\nK = 144.0167\n\nK is the reaction equilibrium constant represented with the formation of oxalic acid dimers in diethyl ether. It gives the degree of dimerization of oxalic acid in diethyl ether.\n\nThis table presents the partition coefficient values of oxalic acid in diethyl ether-water and the concentration of oxalic acid in water. As the concentration of oxalic acid decreases in water, the partition coefficient value increases.\n\nIntercept, kD = 0.07202\n\nslope = −0.01584 = (KkD)1/2\n\nK = α = 0.0035\n\nThis reaction equilibrium constant K represented by α, gives the degree of ionization of oxalic acid in water in this system.\n\nEquation (23) is used.\n\nA plot of CXA/CX∗B(1−α) vs CX∗B(1−α) is a straight line, α is the degree of ionization of oxalic acid in water.\n\nBoth the ionization of oxalic acid in water and its dimerization in diethyl ether respectively are considered.\n\nThus, 1−α= 0.9965\n\nTable 6 shows the effect of ionization on the partition coefficient of oxalic acid in diethyl ether-water. The concentration of oxalic acid increases as the partition coefficient values increase.\n\nkD = 0.01726\n\nslope = 0.08638 = 2kD2K = 0.0005958152K\n\nK = 144.98\n\nThis value gives the combined reactions constant for oxalic acid in diethyl ether-water.\n\nThe values of the partition coefficient (kD) for oxalic acid in n-hexane-water at 30°C and atmospheric pressure were calculated as shown in Table 7.\n\nTable 7 shows the dissolution of oxalic acid in n-hexane and in water in the n-hexane-water system. The partition coefficient value of oxalic acid in this system decreases with the increase in concentration of oxalic acid in the system. Additionally, oxalic acid dissolves more in water than in n-hexane.\n\nIntercept, kD = 0.02793\n\nslope = 2kD2K = −0.03164\n\nK = 20.2798\n\nK is the reaction constant for the degree of formation of the oxalic acid dimers in n-hexane.\n\nThis table relays the concentration of oxalic acid in water and the partition coefficient values of oxalic acid in n-hexane-water. The concentration of oxalic acid in water decreases as the partition coefficient values decrease.\n\nIntercept, kD = 0.01065\n\nslope = 0.00444 = (KkD)1/2\n\nK = α = 0.0019\n\nThis reaction equilibrium constant gives the extent of ionization of oxalic acid molecules in water in this system.\n\nEquation (23) is used.\n\nA plot of CXACX∗B(1−α) vs CX∗B(1−α) is a straight line, α is the degree of ionization of oxalic acid in water.\n\nBoth the ionization of oxalic acid in water, and its dimerization in n-hexane are considered.\n\nThus, 1 − α= 0.9981\n\nTable 9 shows the effect of ionization on the partition coefficient values and on the concentration of oxalic acid in water in the n-hexane-water system. The concentration of oxalic acid in water increases as the partition coefficient value decreases.\n\nkD = 0.02787\n\nslope = −0.03153 = 2kD2K = 0.0015534738K\n\nK = −20.296\n\nThis equilibrium constant gives the combined equilibrium constant for both dimerization and ionization of oxalic acid in n-hexane and water respectively in this system.\n\nFrom Table 10, oxalic acid has the highest partition coefficient value of 0.07383 in carbon tetrachloride-water and the lowest dimerization constant magnitude of 15.7092 also in carbon tetrachloride-water. This makes carbon tetrachloride-water the best binary solvent for the analysis of oxalic acid. Dimerization reactions occurred in the three systems with the highest dimerization constant magnitude of 144.0167 in the diethyl ether-water system. There were low ionization reactions in the three systems. The interfering reactions of dimerization and ionization affect the molecular distributions of oxalic acid in the binary solvents.\n\nThe values of the partition coefficient (kD) for succinic acid in carbon tetrachloride-water at 30°C and atmospheric pressure were calculated as shown in Table 11.\n\nA plot of CXACX∗B against CX∗B from equation (19) gave a straight line (Figure 10) with intercept kD and slope equal to 2kD2K. The dimerization constant, K, was calculated using the slope of the plot according to the relations:\n\nTable 11 shows the dissolution of succinic acid in carbon tetrachloride and in water in this system. Succinic acid dissolves more in water than in carbon tetrachloride. Additionally, the partition coefficient value decreases as the concentration of succinic acid in the system increases.\n\nkD = 0.05617\n\nslope = −0.11715\n\nK = −18.5655\n\nK is the equilibrium constant for the formation of succinic anhydride in carbon tetrachloride.\n\nTable 12 relates the concentration of succinic acid in water and the partition coefficient values in carbon tetrachloride-water. The concentration of succinic acid in water decreases as the partition coefficient value decreases.\n\nkD = −0.05393\n\nslope = 0.03911 = (KkD)1/2\n\nK = 0.0284 = α\n\nThe equilibrium constant K represented by the ionization constant α gives the degree of ionization of succinic acid in water of carbon tetrachloride-water system.\n\nBoth dimerization and ionization reactions occurred with succinic acid solute in the two solvents respectively.\n\nEquation (23) is used.\n\nA plot of CXACX∗B(1−α) vs CX*B(1−α) gives a straight line, α is the degree of ionization of the succinic acid in water.\n\nThus, (1−α) = 0.9716.\n\nTable 13 shows the effect of ionization on the partition coefficient values and on the concentration of succinic acid in water. The concentration of succinic acid increases as the partition coefficient values decrease.\n\nkD = 0.05462\n\nslope = −0.11722 = 2kD2K = 0.0059666888K\n\nK = −19.6457\n\nThis equilibrium constant gives the combined reactions constant for both the succinic anhydride formation and succinate ions formation in this system.\n\nThe values of the partition coefficient (kD) for succinic acid in diethyl ether-water at 30°C and atmospheric pressure were calculated as shown in Table 14.\n\nTable 14 shows the dissolution of succinic acid in diethyl ether and in water. Succinic acid dissolves more in water than in diethyl ether. The partition coefficient values in this system decrease as the concentration of succinic acid in the system increases in water.\n\nIntercept, kD = 0.0427\n\nslope = 2kD2K = −0.06538\n\nK = −18.1611\n\nK is the reaction equilibrium constant for the formation of succinic anhydride in diethyl ether.\n\nTable 15 presents the values for concentration of succinic acid in water and the partition coefficient values in diethyl ether-water. The concentration of succinic acid in water decreases as the partition coefficient values decrease.\n\nIntercept, kD = −0.00814\n\nslope = 0.01643 = (KkD)1/2\n\nK = α = 0.0332\n\nK is the reaction equilibrium constant represented as α for the ionization reaction for the formation of succinate ions in water of this system.\n\nUsing equation (23) a plot of CXACX∗B(1−α) vs CX∗B(1−α) will give a straight line where α is the degree of ionization of succinic acid in water.\n\nThus, (1−α) = 0.9668\n\nThis table shows the effect of ionization on the concentration of succinic acid in water and on the partition coefficient in diethyl ether-water. The partition coefficient decreases as the concentration of succinic acid increases in water.\n\nkD = 0.04122\n\nslope = −0.06514 = 2kD2K = 0.0033981768K\n\nK = −19.17.\n\nK is the equilibrium constant for the combined reactions of anhydride formation and succinate ions formation in this system.\n\nThe values of the partition coefficient (kD) for succinic acid in n-hexane-water at 30°C and atmospheric pressure were calculated as shown in Table 17\n\nTable 17 shows the dissolution of succinic acid in n-hexane and in water. Succinic acid dissolves more in water than in n-hexane, and the partition coefficient value increases with the increase in the concentration of succinic acid in the system.\n\nIntercept, kD = −0.04274\n\nslope = 2kD2K = 0.26286\n\nK = 71.9491\n\nK is the equilibrium constant for the formation of succinic anhydride in n-hexane.\n\nTable 18 relates the concentration of succinic acid in water and the partition coefficient in n-hexane-water. The concentration of succinic acid in water decreases as the partition coefficient values increase.\n\nIntercept, kD = 0.15664\n\nslope = −0.06448 = (KkD)1/2\n\nK = α = 0.0265\n\nK gives the reaction equilibrium constant for the ionization of succinic acid, α, in water in this system.\n\nUsing equation (23) a plot of CXACX∗B(1−α) vs CX∗B(1−α) will give a straight line, α is the degree of ionization of succinic acid in water.\n\nThus, (1 − α) = 0.9735\n\nTable 19 shows the effect of ionization on the concentration of succinic acid in water and on the partition coefficient values in n-hexane-water. The concentration of succinic acid in water increases linearly; the partition coefficient increases too with the increase in concentration of succinic acid in the system.\n\nkD = −0.04161\n\nslope = 0.26278 = 2kD2K = 0.0034627842K\n\nK = 75.89\n\nThis is the equilibrium constant for the combined reactions for the formation of succinic anhydride and succinate ions in this system.\n\nSuccinic acid has the partition coefficient (kD) values of −0.0562 in carbon tetrachloride-water, 0.0427 in diethyl ether-water and −0.0427 in n-hexane-water, as shown in Table 20. The formation of succinic anhydride occurred in the three systems with the highest value of 71.9491 occurring in the n-hexane-water medium. The ionization reaction in the three systems was relatively low. Carbon tetrachloride-water is the best binary immiscible solvent for succinic acid analyses from the three systems that were investigated.\n\n\nConclusion\n\nThis research emphasizes the use of binary immiscible solvents in the extraction of solutes from contaminants and from the ores. Carbon tetrachloride-water is recommended for the analyses of both oxalic acid and succinic acid.\n\nFrom the results in Table 10, oxalic acid has the highest partition coefficient value of 0.0738, the dimerization constant value of 15.7092, in magnitude, and the ionization constant value of 0.0303. These values show that extraction of oxalic acid in carbon tetrachloride is possible. Additionally, there were interfering dimerization reactions in the carbon tetrachloride, and ionization reactions of the oxalic acid in the water. This is similar to the case of succinic acid with the highest partition coefficient value of 0.0562, in magnitude, and with the dimerization constant value of 18.5655 in magnitude, and ionization constant value of 0.0284. The extraction of succinic acid with carbon tetrachloride is possible.\n\nThe reaction conditions of 30°C and atmospheric pressure were used for this research. In future research, we recommend a variety of temperature and pressure conditions are used in order to determine the best temperature for these extractions.\n\nSome challenges were faced in the process of this research, including having a steady network for studies and taking precautionary measures while analyzing the solutes to avoid their excessive inhalations.\n\nPartition coefficient technique is a good analytical parameter for the analyses of materials in binary immiscible solvent. The partition coefficient value resulting from the use of binary immiscible solvent serves as a tool to underscore the efficiency of the partition coefficient technique. Other parameters such as dimerization constant, K, ionization constant, α, also show the degree and efficiency of the process. Partition coefficient technique is an excellent method of purification, and extraction of solutes, from binary immiscible solvents. A high partition coefficient shows that there is dissolution of the solute in the solvent involved, and therefore good separation is assured.\n\nThe equation,\n\nis the general equation for the consideration of the effects of solute interactions in binary immiscible solvent used in the solvent extractions. Thus,\n\nPartition coefficient technique is the efficient method for purification, beneficiation, and extraction of materials from the impure state. It is recommended for laboratories, and industries for the analyses of materials in binary immiscible solvents, for purification of impure substances, and for concentration of substances and for the beneficiation of materials from the impure states.\n\nSystems left alone in nature run down to a stage where the observable properties that describe such systems become independent of time. Examples of such systems are:\n\n1 Heat flows from a hot body to a cold body until both bodies have similar temperatures.\n\n2 Matter diffuses from a position of high concentration to a position of low concentration until the concentrations become even.\n\n3 Water runs down the hill\n\n4 A ball dropped on a pavement eventually stops bouncing.\n\n5 A mixture of hydrocarbon gas and air burns to give water and carbon dioxide and later the reaction stops.\n\nIn all of these examples above, there is a difference in the property of the system which could be described as property gradient. There is property gradient formed in the manner of temperature gradient from state 1 to state 2 (T1 to T2), in the manner of concentration gradient, from concentration 1 to concentration 2 (C1 to C2) etc. These natural processes occur with no loss of energy by the system, they occur of their own accord and are spontaneous and irreversible. All naturally occurring processes always change spontaneously in a direction that leads to equilibrium and the driving force lies at the heart of thermodynamics with special emphasis on increase in entropy. The maximum work a process may perform is the true measure of the driving force that accompanies the process.\n\nThe concept of property gradient observed in the natural processes above is created by the use of binary immiscible solvents with differential solubilities of a solute in the solvents. The driving force is defined by the partition coefficient. When a binary immiscible solvent is used as discussed in this work, efficiency of solvent extraction is enhanced.\n\n\nData availability\n\nZenodo: Comparisons of the effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents: a case of oxalic acid and succinic acid. https://doi.org/10.5281/zenodo.5171412.28\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nOnyeocha VO, Akpan OD, Onuchukwu IA, et al.: The Dimerization Effects of Some Solutes on the Partition Coefficient (kD) in Binary Immiscible Solvents. Intern. Lett. Chem. Phys. Astrono. 2018; 80: 40–52. Publisher Full Text Reference Source\n\nOnuchukwu AI: Chemical Thermodynamics for Science Students. Owerri:FUTO Press; 4th ed.2016; 175.\n\nRastogi RP, Misra RR: An Introduction to Chemical Thermodynamics. India:Vikas Publishing House Pvt Ltd; Second Edition.1980; pp 296–300.\n\nStaunton S, Geoderma: Sensitivity Analysis of the Distribution Coefficient, kD, of Nickel with Changing Soil Chemical Properties.Oct 2004.\n\nOthmer K: Encyclopaedia of Chemical Technology.1979; Vol, 1: pp 147. Third Edition.\n\nMorrison RT, Boyd RN: Organic Chemistry. Sixth Edition;2005; 375.\n\nAston JG, Fritz JJ: Thermodynamics and Statistical Thermodynamics. New York:John Wiley and Sons Inc;1963; 105.\n\nSmith JM, Van Ness HC: Introduction to Chemical Engineering Thermodynamics. New York:McGraw-hill Book Company; Fifth ed.1996; 225.\n\nJerry M: Advanced Organic Chemistry, Reactions, Mechanisms and Structure. New York:John Wiley and Sons Inc;Second ed2003; 307.\n\nGraham Solomons TW: Organic Chemistry. New York:Third Edition;1984; 375.\n\nAtkins P, Jones L: Chemistry Molecules, Matter and Change. New York:Sumanas, Inc., and W. H. Freeman and Company;Third Edition1997; pp 437–463, 490.\n\nKeolopile ZG, Ryder MR, Gutowski M: Intermolecular Interactions between Molecules in Various Conformational States: The Dimer of Oxalic Acid. J. Phys. Chem. A. 2014; 118: 7385, 7385-7391, June 13, 2014. Publisher Full Text\n\nDingrando L, Tallman KG, Hainen N, et al.: Chemistry Matter and Change. New York:The McGraw-Hill Companies, Inc.;2005; 452–486.\n\nSnell-Hilton: Encyclopaedia of Industrial Chemical Analysis.1979; 4: 101.\n\nOnuchukwu AI: Electrochemical Technology. Ibadan:Spectrum Books Limited;2008; 33–35.\n\nPhilips JS, Strozak VS, Wistrom C: Chemistry Concepts and Applications. New York:Glencoe/McGraw-Hill;2005; 451–472.\n\nDavis RE, Frey R, Sarquis M, et al.: Modern Chemistry. New York:A Harcourt Education Company;Teacher Edition.pp 400–425, 498-522.\n\nAtkins P, de Paula J : Physical Chemistry. New York:W. H. Freeman and Company;2002; pp 161–175.\n\nAtkins P: Physical Chemistry. New York:W. H. Freeman and Company;Fifth ed1993; 213–231.\n\nFong P: Foundation of Thermodynamics. New York:Oxford University Press;1963; 73.\n\nManhan BH: Elementary Chemical Thermodynamics. Third ed.New York:W. A. Benjamin Inc;1963; 207.\n\nLambert J, Muir TA: Practical Chemistry. London:Heinemann Educational Book Ltd;Third ed.1973; 273.\n\nMei PR, Moreira SP, Cortes ADS, et al.: Determination of the effective distribution coefficient for silicon impurities. J. Renew. Sustain. Ener. 2012; 4: 043118. Publisher Full Text\n\nTetko IV, Poda GI: Application of ALOGPS 2.1 to predict log kD Distribution Coefficient for Pfizer proprietary Compounds. J. Med. Chem. 2004; 47: 5601–5604. PubMed Abstract | Publisher Full Text\n\nKodolikar-Kulkarni S, Bhatkhande D: Prediction of effectiveness of solvent using distribution coefficient calculation in solvent extraction with the help of Hansen solubility parameters.2020.\n\nBarnes N, Gramajo de Doz M, Solimo HN: Liquid-liquid extraction of oxalic acid from aqueous solutions with tributyl phosphate and a mixed solvent at 303.15K.1999.\n\nLaboratory Chemicals and Biochemical (BDH)1982; pp 220. Export Edition.\n\nOnyeocha VO: Comparisons of the effects of solute interactions on partition coefficient, kD, in selected binary immiscible solvents: a case of oxalic acid and succinic acid.2021. Publisher Full Text\n\nNicholas P: Cheremisinoff, Motasem B. Haddadin, Beyond Compliance. Gulf Publishing Company;2006. Publisher Full Text"
}
|
[
{
"id": "120391",
"date": "21 Apr 2022",
"name": "Shilpa Prasad Kodolikar",
"expertise": [
"Reviewer Expertise Liquid separations",
"process design",
"mathematical modeling and simulation",
"ionic liquids"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript describes the methodology for partition coefficient predictions based on molecular distribution of solutes. The overall approach is well appreciated.\nSome redeeming features are the molecular distribution approach selection for partition coefficient technique, well defined objective of all methodology, successful implementation and application of technique to industrial systems.\nSome points to revisit can be including some latest literature, post 2018, reconstructing some sentences [pg 5 para 1 line 2]. Overall the paper is good.\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": "161096",
"date": "22 Mar 2023",
"name": "Ana C. Gomez Marigliano",
"expertise": [
"Reviewer Expertise thermodymanics"
],
"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 work that I consider adequate, due to the number of tests carried out and the possible applications at an environmental level that derive from the results. However, I have a few recommendations.\nIn page 3 – line 1 and line 6, write \"immiscible solvent binary system\" instead of “binary solvent system”. In page 3, after equation 4: only in A? The solvent strength really needs to be much greater or much less than one to be efficient...check the equation 15. Must give purity of reagents and uncertainties of the results obtained and also the instruments used to measure temperature and pressure. When you made the composition measurements of each phase. How are you sure that it reached equilibrium? Results must be given with uncertainty.\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?\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/11-63
|
https://f1000research.com/articles/11-62/v1
|
19 Jan 22
|
{
"type": "Systematic Review",
"title": "Effectiveness of low-dose radiation therapy in COVID-19 patients globally: A systematic review",
"authors": [
"Sirish Raj Pandey",
"Saroj Adhikari Yadav",
"Swotantra Gautam",
"Kalpana Giri",
"Anirudra Devkota",
"Shipra Shrestha",
"Shreya Bhandari",
"Santosh Baniya",
"Bibhuti Adhikari",
"Bibek Adhikari",
"Shila Neupane",
"Jenish Bhandari",
"Sirish Raj Pandey",
"Swotantra Gautam",
"Kalpana Giri",
"Anirudra Devkota",
"Shipra Shrestha",
"Shreya Bhandari",
"Santosh Baniya",
"Bibhuti Adhikari",
"Bibek Adhikari",
"Shila Neupane",
"Jenish Bhandari"
],
"abstract": "Background: Novel Corona Virus Disease 2019 (COVID-19) can affect multiple organs, including the lungs, resulting in pneumonia. Apart from steroids, other anti-COVID drugs that have been studied appear to have little or no effect on COVID-19 pneumonia. There is a well-known history of inflammatory disease, including pneumonia, treated with low-dose radiation therapy (LDRT). It reduces the production of proinflammatory cytokines, Interleukin-1a (IL-1a), and leukocyte recruitment.\n\nMethods: A comprehensive literature search was conducted using PubMed, Scopus, Embase, CINAHL, and Google Scholar, with keywords such as “radiotherapy,” “low-dose radiation therapy,” “low-dose irradiation,” “covid-19 pneumonia,” “SARS-CoV-2 pneumonia,” and “covid pneumonia.” with additional filters for human studies and customized articles in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We reviewed randomized controlled trials, quasi-experimental studies, cohort, case-control, and cross-sectional studies with a clearly defined intervention, including low-dose radiotherapy alone or in combination with any therapy to treat COVID-19 pneumonia from December 2019 to May 2021. Patients receiving standard or high-dose radiotherapy, including for other diseases, were excluded. Zotero software was used to collect and organize research from various databases, remove duplicates, extract relevant data, and record decisions. Participants’ demographics and baseline status were obtained from the full-text articles along with the intervention’s outcome/effect on patient status. Results: Four studies with 61 participants that met the inclusion criteria were included. One was a double-blind randomized controlled trial, one a non-randomized trial, while the other two were single-arm clinical trials. Low-dose radiation therapy did not show any significant improvement in COVID-19 patients. Conclusion: Only two studies included in this review demonstrated an improvement in inflammatory markers; however, patients were also given steroids or other drugs. Therefore, the confounding effects must be considered before drawing conclusions. This systematic review does not support mortality benefit, clinical course improvement, or imaging changes with LDRT.",
"keywords": [
"COVID-19 pneumonia",
"CT-scan",
"low-dose radiation therapy",
"LDRT",
"systematic review"
],
"content": "Introduction\n\nThe novel coronavirus disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to global catastrophe since December 2019.1 Mostly COVID-19 (coronavirus disease 2019) patients are asymptomatic or present with mild to moderate symptoms. Some patients, however, may present with severe symptoms and quickly deteriorate to end-organ failure or acute respiratory distress syndrome (ARDS).2,3 The ICU (Intensive Care Unit) settings management has shown improvements in the survival of patients.4 Still, the management has remained primarily supportive, and more intervention and treatment options are required for severe and critically ill patients in ICU.5 Studies have shown diffuse alveolar damage with inflammatory infiltrates in postmortem analysis of COVID-19 patients, which compromises the gas exchange.6 The mortality rate among critically ill patients in ICU still remains as high as 30–40% globally.7 Mortality up to 80% is seen once a COVID-19 patient is dependent on mechanical ventilation.8–10 ARDS leading to respiratory failure is the most common cause of mortality among COVID-19 patients.11\n\nViral pneumonia can result in systemic inflammation and multiorgan failure due to cytokine storms caused by a severe inflammatory response in the body.12 Such excessive host immune response and direct viral damage can not only cause significant lung injury and diffuse alveolar damage but also have a reaction like local microvascular thrombosis and raised inflammatory markers.6,13 Remdesivir and other studied antiviral drugs did not significantly affect overall mortality,5 the World Health Organization has recommended not using these drugs based on the latest studies.14\n\nOne novel approach suggested for COVID-19 patients is the whole-lung LDRT (low-dose radiation therapy).15 LDRT has anti-inflammatory properties like lowering proinflammatory cytokine levels (e.g., Interleukin 1a (IL-1a)) and inhibiting the recruitment of leukocytes.16–19 Hence, since the 20th century, LDRT has been used to manage inflammatory disorders, including pneumonia, with several studies showing potential benefits.15,20 The evidence of management of viral pneumonia in the past has led to the proposal of LDRT as a possible intervention to manage COVID-19 pneumonia.21,22 Numerous prior studies have described the mechanism of how LDRT can provide a therapeutic advantage.14,23–29 However, the efficacy of LDRT is not well studied for the treatment of COVID-19 pneumonia.5 Because of the limited treatment options for COVID-19 and the minimal risk of toxicity, several clinical trials of LDRT for COVID-19 management are being carried out with 0.3 to 1.5 Gy (Gray) radiation doses.30,31\n\nWe conducted a systematic review to evaluate the clinical and radiological effects of LDRT in patients with severe acute respiratory syndrome (SARS) due to COVID-19.\n\n\nMethods\n\nThis systematic review was performed to analyze the effectiveness of LDRT for COVID-19 pneumonia patients globally. This review was registered on PROSPERO on 6th March 2021 (CRD42021258776).\n\nThese criteria were sought for inclusion in the study:\n\nA) Population: COVID-19 patients globally.\n\nB) Intervention: Low dose radiotherapy/low dose radiation therapy with any combination of treatment for COVID-19 pneumonia.\n\nC) Comparison with a control group in the study.\n\nD) Outcomes: Improvement in lung consolidation (chest X-ray and CT scans) and inflammatory markers (level of cytokines, I.L./Interleukins, e.g., IL6), O2 saturation levels, C-reactive protein (CRP))\n\nE) Study Design: Randomised controlled trial (RCT), cohort, cross-sectional, case-control, quasi-experimental, case studies.\n\nWe included randomized controlled trials (RCTs), quasi-experimental studies and cohort, case-control, cross-sectional studies with a clearly defined intervention published between December 2019 and May 2021. We excluded case reports, reviews, perspective/opinion articles, newspaper articles, book chapters/medical books.\n\nTwelve reviewers conducted study selection (SRP, SB1, AD, JB, SB2, SS, Bibh. A, KG, SG, SAY, Bibe. A, SN). Zotero software (version 5.0.96.2) was used to assemble and organize the studies obtained through the various databases. All ten reviewers then screened the titles and abstracts of the studies in four groups, with two members in each group. Duplicate studies were removed. Five reviewers, SRP, SB1, AD, JB, and SB2, independently screened records for inclusion. Four reviewers, SRP, SS, Bibh. A, and KG, checked the decisions. We included human studies involving both sexes in which patients received low-dose radiation therapy to treat COVID-19 pneumonia. The risk of bias and quality of studies was assessed by the Cochrane risk-of-bias tool for randomized trials version 2 (RoB 2), Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I), and the National Institute of Health (NIH) quality assessment tools for before-after studies with no control group. Any confusion or disagreements were resolved among all the members. Four reviewers, SRP, SG, SAY, and KG discussed the results and prepared the first draft of the manuscript, and five reviewers, SRP, SAY, SG, Bibe. A and SN reviewed subsequent edits. The full-text articles were screened to obtain the following data: author, year of publication, study design, study setting, participant demographics and baseline status, type, duration and times of intervention, and outcome/effect on the patient status following the intervention. We also extracted the primary outcomes, which were the number of deaths or discharges following the intervention, and the secondary outcomes, which were the oxygen status of the patients, CT-scan changes, and requirement for mechanical ventilation following the intervention. We also determined any toxicity of the intervention and changes in inflammatory markers.\n\nA comprehensive literature search was performed on the following databases: PubMed, Scopus, Embase, CINAHL (Cumulative Index of Nursing and Allied Health Literature), and Google Scholar using relevant Medical Subject Headings (MeSH) and keywords termed “radiotherapy,” “low-dose radiation therapy,” “low-dose irradiation,” “covid-19 pneumonia”, “SARS-CoV-2 pneumonia”, “covid pneumonia”, and “coronavirus pneumonia” with additional filters of human studies and English language (Please see underlying data32). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to search for the studies which evaluated the role of the effectiveness of low-dose radiation therapy for COVID-19 pneumonia patients globally. Five reviewers, SRP, SB1, AD, JB, and SB2, independently screened records for inclusion. Four reviewers, SRP, SS, BA, and KG checked decisions to include articles. In case of dissent, all the reviewers re-evaluated the inclusion and exclusion criteria, and the final decision was made based on the majority’s judgment. The PRISMA checklist 2020 was followed throughout the process.32\n\nFor the RCTs, we used the Cochrane risk-of-bias tool for randomized trials (RoB 2) to assess any bias in the randomization process, any deviation from the intended intervention, missing outcome data, measurement of the outcome, selection of reported results, and overall risk of bias. The ROBINS-I Risk of Bias in Non-Randomized Studies - of Interventions was used to assess bias due to confounding, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, and measurement of measurement outcomes, selection of the reported result. The National Institute of Health (NIH) quality assessment tools were used for the before-after study with no control group for single-arm studies. Seven reviewers, SRP, KG, AD, SS, SB1, Bibh. A, and SB2 were involved in the risk of bias assessment.\n\n\nResults\n\nThe search using the appropriate terms yielded 1644 potentially relevant articles from Pubmed, Scopus, CINAHL, Google Scholar, and Embase. Through the database search, we found 1644 studies, and 351 among them were identified as duplicates and removed. We screened 1293 studies with titles and abstracts and excluded 1227 studies among them. Then the remaining 66 studies were thoroughly assessed for full-text eligibility. Finally, a total of four studies were listed for the qualitative analysis. This information is visually presented in the PRISMA flow diagram (Figure 1).\n\nSanmamed et al. (2021) studied the effects of 100 cGy radiotherapy on total lungs in a single fraction on patients who were COVID-19 positive, at phase two or three by lung involvement or oxygen requirement. The authors suggested that low-dose radiotherapy could also be a treatment option even after 14 days if the anti-COVID treatment fails. However, there is a possible confounding effect of prior anti-COVID therapy with steroids, hydroxychloroquine, lopinavir/ritonavir, tocilizumab, or remdesivir in this study. The limited number of patients and it being a single-arm study are other limitations.31\n\nA trial conducted in Georgia, USA (Hess et al., 2021) studied the effects of 1.5 Gy radiotherapy on both lungs of COVID-19 patients. They selected ten patients that were oxygen-dependent and non-intubated. The control group was chosen from a separate trial conducted in another institution among COVID-19 positive patients. They were matched with the intervention group by age and comorbidities and were given supportive treatment with or without anti-COVID drug therapy. Four patients in the intervention group received azithromycin, one received steroids, and all ten received primary supportive care; hence, the study has possible confounding effects.33\n\nIn Tehran, Iran, Ameri et al., 2021 studied the effects of 0.5 or 1.0 Gy single fraction low-dose whole-lung irradiation (LD-WLI) in 10 patients with moderate COVID-19 pneumonia. Five patients received 0.5 Gy single fraction radiotherapy, four received 1 Gy single fraction radiotherapy, and one received 0.5 Gy radiation twice; a second therapy was given after clinical deterioration following the first few days of improvement.34\n\nResearchers in Switzerland (Papachristofilou et al., 2021) conducted a double-blinded randomized controlled trial in which 22 patients were randomized in two groups with 11 patients in each, receiving 1 Gy low-dose radiation vs. sham radiation. The study did not significantly improve ventilator-free days after 15 days, overall survival, PaO2/FIO2 ratio, and inflammatory markers when compared among two groups. The lymphocyte reduction was significant in the low-dose radiation group in comparison. The authors indicated no role of low-dose radiotherapy in treating COVID-19 pneumonia.5 The major study characteristics are tabulated in Table 1.\n\nWe included four studies, which had different study designs. Therefore, we applied different risk of bias assessment tools for different studies. Studies one (Sanmamed et al., 2021) and three (Ameri et al., 2021) were single-arm before and after studies,31,34 study two (Hess et al., 2021) was quasi-experimental,33 and study four (Papachristofilou et al., 2021) was an RCT.5 For studies one and three, we used the National Institute of Health (NIH) quality assessment tools for before-after studies with no control group for single-arm studies. According to the NIH quality assessment tool, we found both studies to have fair risk of bias. The assessments of Sanmamed et al.,31 and Ameri et al.,34 are presented in Table 2. For study 2 (Hess et al., 2021), we used the Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I)37 and found the study to have a moderate risk of bias. We generated a traffic light plot and summary of the assessment, presented in Figure 2. In study 4 (Papachristofilou et al., 2021), we used the Cochrane risk-of-bias tool for randomized trials version 2 (RoB 2).5 We found the study to have a low risk of bias (Figure 3).32\n\n* CD (Cannot determine); N.A. (Not applicable); N.R. (Not reported).\n\nIn study one (Sanmamed et al., 2021), there was a decrease in the acute phase reactants after one week of radiotherapy but compared to baseline, only lactate dehydrogenase (LDH) showed a significant decline (P = 0.04). The preliminary report also showed significant improvement in the SatO2/FiO2 index (SAFI). Seven patients were discharged, maintaining supplemental oxygen (maximum 3L).31\n\nThe intervention group showed earlier clinical recovery and discharge in study two (Hess et al., 2021). The 28-day overall survival had no significant difference, while freedom from intubation was 90% vs. 60% (P = 0.16). Lower oxygen requirement at the time of intervention and less time to clinical recovery (P = 0.01) were needed by patients aged 65 or over in the intervention group. Still, no significant changes in the control group were observed. Neither group showed significant improvement in radiographic imaging. The study showed a significant reduction in inflammatory biomarkers (C-reactive protein (CRP) and LDH), cardiac markers, white blood cells. There was a considerable lack of leukocytosis in the intervention group compared to the control group. Although not significant, the study suggested the possibility of prevention of elevation of hepatic biomarkers by low-dose radiotherapy.33\n\nIn study three (Ameri et al., 2021), the overall clinical recovery shown by the study was 60%. Still, there was no significant improvement in clinical recovery and SpO2 among both groups of radiation dose patients. In the trial, four patients died before discharge, and two died immediately after being discharged. Patients who survived showed some improvement in the inflammatory markers.34\n\nIn study four (Papachristofilou et al., 2021), the study did not significantly improve ventilator-free days after 15 days, overall survival, PaO2/FIO2 ratio, and inflammatory markers when compared among the two groups. The lymphocyte reduction was significant in the low-dose radiation group in comparison.5\n\nThe major outcomes of the review are summarized in Table 3, where descriptive comparative data are presented as the same measures were not followed throughout all four studies.\n\n\nDiscussion\n\nTwo of our included studies indicated improvement in inflammatory markers to some extent with low dose radiotherapy, but these studies also prescribed steroids or other drugs like azithromycin, hydroxychloroquine, tocilizumab, remdesivir to patients31,33; the two other studies did not show any significant improvement.5,33 LDRT has been used to treat various acute and chronic inflammatory diseases since 1900; Musser and Edsall introduced radiotherapy to treat pneumonia in 1905.35 The mechanism of single LDRT (0.2 to 1.0) proved to be highly effective in treating pneumonia. It involved the induction of an anti-inflammatory phenotype that led to rapid clinical improvements and markedly reduced mortality risk.15 COVID-19 patients with severe pulmonary diseases have increased expressions of inflammatory markers such as C-reactive protein, ferritin, elevated D dimers, and proinflammatory cytokines.36 In such cases, low-dose radiation therapy could provide a therapeutic arsenal against COVID-19-related complications and associated morbidity and mortality.37 COVID with ARDS requires oxygen and ventilatory support, yet mortality during mechanical ventilation is high despite such measures.36 COVID-19 can cause inflammation in the lungs, hypoxemia, and increased breathing. Patients may need early intubation, further damaging the lungs.38 In such cases, several inflammatory conditions, including bacterial/viral pneumonia, have been successfully treated with radiation therapy.39\n\nThe study by Sanmamed et al. showed significant improvement in extension score between the first simulation computed tomography (CT) scan and day seven CT-scan after radiotherapy (p = 0.03). Still, no significant difference was found in severity score by imaging.31 Other studies did not follow nor study CT-scan changes homogeneously before and after radiotherapy.5,33,34 Hence, our review could not determine if LDRT plays any role in bringing significant changes/improvement in C.T. chest findings in COVID-19 pneumonia. The features of the chest C.T. of COVID patients depend on scanning time, age of the patient, the condition of disease during follow-up, immune status of the patient, drug therapy provided, and the underlying pathology.40 The most common findings of C.T. are ground-glass opacity at peripheral and lower lobes, patchy consolidations in multiple areas with the peripheral and central distribution.40,41\n\nThree of the included studies showed reduced white blood cells, especially lymphocytes, essential for resistance against COVID-19. These three studies also used other anti-COVID drugs like steroids such as dexamethasone, remdesivir, or monoclonal antibodies.5,31,33 Dexamethasone can cause lymphopenia,42 but our review has no concrete evidence as to what caused the reduction of white blood cells. Remdesevir has shown an improved rate of clinical recovery in COVID-19 patients.43\n\nStudies regarding the toxicity of LDRT suggest that doses lower than 1 Gy may not majorly concern short-term or long-term follow-up.39 The risk of radiation injury in medical imaging has been discussed in the past and hovers between 10 mSv to 100 mSv.44 but, according to the 2006 BEIR VII lifetime attributable cancer risk model, 1 in 1000 can develop cancer with a radiologic procedure dose of 10 mSv.45 However, evidence suggests that the radiation dose of 0.15–1.5 Gy is linearly related to solid cancer induction (i.e., a range of approximately 1 log).46 Ameri et al. suggest LDRT (<1 Gy) can yield anti-inflammatory effects, while more than 1 Gy can enhance the proinflammatory development and requires more extensive study.34 Various experiments in cats and mice exposed to 0.5–1 Gy 24h after virus inoculation showed a beneficial protective effect.39 Treatment with LDRT suggests improved cytokine release syndrome, a significant reduction in total leukocyte counts, serum creatinine, serum liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).39 For COVID-19 patients that present with a cytokine storm, a single total dose of 0.3–0.5 Gy targeted radiotherapy is beneficial in reducing the possibility of any immediate or long-term adverse effects.24\n\nA recovery trial showed lower 28-day mortality among those receiving invasive mechanical ventilation or oxygen alone at randomization with dexamethasone.13 Hence, this steroid is a proven medication with a mortality benefit at the moment. However, Dexamethasone also has several side effects like hormonal imbalance, weight gain, fluid retention, anxiety, disturbed sleep patterns, withdrawal symptoms, etc. There is a risk of fungal infection, as recently seen with a rise in Mucormycosis cases in India (steroid side effects)47 Thus, having LDRT as a treatment option for those who are not ideal candidates for steroids could prove to be a boon.\n\nThe studies included in this review have a limited number of patients, mainly assessed in a single facility. They cannot, therefore, truly determine the actual effect on the general population. The included studies also used different methods, including two single-arm studies, one RCT, and one non-randomized (Quasi-experimental) study.5,31,33,34 Although two studies showed some improvement regarding inflammatory markers, and one showed improvement in extension score before concluding, we must also consider the possibility of confounding effects by using drugs capable of anti-inflammatory effect dexamethasone and remdesivir.43,48,49 All the included studies do not have thorough follow-up information about ventilator use and their outcome either, so it is hard to make any firm conclusions about how LDRT can bring about changes to lung status during COVID pneumonia.\n\n\nConclusion\n\nOnly two studies included in this review demonstrated an improvement in inflammatory markers; however, patients were also given steroids or other drugs. Therefore, the confounding effects must be considered. This systematic review does not support any clinical benefit from LDRT. As of now, this systematic review of the available literature does not provide sufficient evidence to back up any mortality benefit, improvement in the clinical course, or imaging changes with LDRT. As a possible alternative treatment, we suggest large-scale studies with proper dose calculations and greater vigilance of the short-term and long-term beneficial effects and toxicity.\n\n\nData availability\n\nFigshare: Underlying data for ‘Effectiveness of low-dose radiation therapy in COVID-19 patients globally: A systematic review’ https://doi.org/10.6084/m9.figshare.c.5757326.v132\n\nThis project contains the following underlying data:\n\n• Data Extraction\n\n• Search strategy and authors role\n\n• PubMed search details\n\n• Risk of bias assessment of study 1 and 3 (word file created following the NIH quality assessment tool guideline)\n\n• Risk of bias assessment of study 2 (ROBIN-I)\n\n• Risk of bias assessment for study 4 (ROB-2)\n\n\nReporting guidelines\n\nFigshare: PRISMA checklist for ‘Effectiveness of low dose radiation therapy in COVID-19 patients globally: A systematic review’. https://doi.org/10.6084/m9.figshare.c.5757326.v132\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)",
"appendix": "Acknowledgements\n\nWe are highly thankful to our collaborators from ‘Health Action and Research’ – Dr Rolina Dhital, Dr Richa Shah, Dr Carmina Shrestha.\n\n\nReferences\n\nPowell EV: Roentgen therapy of lobar pneumonia. J. Am. Med. Assoc. 1938 Jan 1; 110(1): 19–22. 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 Feb 15; 395(10223): 507–513. PubMed Abstract | Publisher Full Text\n\nWu C, Chen X, Cai Y, et al.: Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020 Jul 1; 180(7): 934–943. PubMed Abstract | Publisher Full Text\n\nDennis JM, McGovern AP, Vollmer SJ, et al.: Improving Survival of Critical Care Patients With Coronavirus Disease 2019 in England: A National Cohort Study, March to June 2020*. Crit. Care Med. 2021 Feb; 49(2): 209–214. PubMed Abstract | Publisher Full Text\n\nPapachristofilou A, Finazzi T, Blum A, et al.: Low-Dose Radiation Therapy for Severe COVID-19 Pneumonia: A Randomized Double-Blind Study. Int. J. Radiat. Oncol. Biol. Phys. 2021 Aug 1; 110(5): 1274–1282. PubMed Abstract | Publisher Full Text\n\nCarsana L, Sonzogni A, Nasr A, et al.: Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect. Dis. 2020 Oct 1; 20(10): 1135–1140. PubMed Abstract | Publisher Full Text\n\nArmstrong RA, Kane AD, Kursumovic E, et al.: Mortality in patients admitted to intensive care with COVID-19: an updated systematic review and meta-analysis of observational studies. Anaesthesia. 2021 Apr; 76(4): 537–548. PubMed Abstract | Publisher Full Text\n\nHuang C, Wang Y, Li X, et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15; 395(10223): 497–506. PubMed Abstract | Publisher Full Text\n\nBhatraju PK, Ghassemieh BJ, Nichols M, et al.: Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. N. Engl. J. Med. 2020 May 21; 382(21): 2012–2022. PubMed Abstract | Publisher Full Text\n\nAuld SC, Caridi-Scheible M, Blum JM, et al.: ICU and Ventilator Mortality Among Critically Ill Adults With Coronavirus Disease 2019. Crit. Care Med. 2020 May 26; 48: e799–e804. PubMed Abstract | Publisher Full Text\n\nRuan Q, Yang K, Wang W, et al.: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May 1; 46(5): 846–848. PubMed Abstract | Publisher Full Text\n\nMehta P, McAuley DF, Brown M, et al.: COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28; 395(10229): 1033–1034. PubMed Abstract | Publisher Full Text\n\nRECOVERY Collaborative GroupHorby P, Lim WS, et al.: Dexamethasone in Hospitalized Patients with Covid-19. N. Engl. J. Med. 2021 Feb 25; 384(8): 693–704. PubMed Abstract | Publisher Full Text\n\nKern PM, Keilholz L, Forster C, et al.: Low-dose radiotherapy selectively reduces adhesion of peripheral blood mononuclear cells to endothelium in vitro. Radiother. Oncol. 2000 Mar 1; 54(3): 273–282. PubMed Abstract | Publisher Full Text\n\nCalabrese EJ, Dhawan G: How Radiotherapy Was Historically Used To Treat Pneumonia: Could It Be Useful Today?. Yale J. Biol. Med. 2013 Dec 13; 86(4): 555–570. PubMed Abstract\n\nRödel F, Keilholz L, Herrmann M, et al.: Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy. Int. J. Radiat. Biol. 2007 Jan 1; 83(6): 357–366. PubMed Abstract | Publisher Full Text\n\nRoyo LT, Redondo GA, Pianetta MÁ, et al.: Low-Dose radiation therapy for benign pathologies. Rep. Pract. Oncol. Radiother. 2020; 25(2): 250–254. PubMed Abstract | Publisher Full Text\n\nSchaue D, Jahns J, Hildebrandt G, et al.: Radiation treatment of acute inflammation in mice. Int. J. Radiat. Biol. 2005 Sep; 81(9): 657–667. Publisher Full Text\n\nArenas M, Gil F, Gironella M, et al.: Time course of anti-inflammatory effect of low-dose radiotherapy: Correlation with TGF-β1 expression. Radiother. Oncol. 2008 Mar 1; 86(3): 399–406. PubMed Abstract | Publisher Full Text\n\nOppenheimer A: Roentgen therapy of interstitial pneumonia. J. Pediatr. 1943 Nov 1; 23(5): 534–538. Publisher Full Text\n\nKirkby C, Mackenzie M: Is low dose radiation therapy a potential treatment for COVID-19 pneumonia?. Radiother. Oncol. 2020; 147: 221. PubMed Abstract | Publisher Full Text\n\nKefayat A, Ghahremani F: Low dose radiation therapy for COVID-19 pneumonia: A double-edged sword. Radiother. Oncol. 2020 Jun; 147: 224–225. PubMed Abstract | Publisher Full Text\n\nHildebrandt MP, Seed CN, Freemantle CAS, et al.: Mechanisms of the anti-inflammatory activity of low-dose radiation therapy. Int. J. Radiat. Biol. 1998 Jan 1; 74(3): 367–378. PubMed Abstract | Publisher Full Text\n\nCalabrese E, Dhawan G, Kapoor R, et al.: Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose. Hum. Exp. Toxicol. 2019 Aug 1; 38(8): 888–898. PubMed Abstract | Publisher Full Text\n\nArenas M, Sabater S, Hernández V, et al.: Anti-inflammatory effects of low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved. Strahlenther Onkol Organ Dtsch Rontgengesellschaft Al. 2012 Nov; 188(11): 975–981. Publisher Full Text\n\nGyuleva I, Djounova J, Rupova I: Impact of Low-Dose Occupational Exposure to Ionizing Radiation on T-Cell Populations and Subpopulations and Humoral Factors Included in the Immune Response. Dose-Response Publ. Int. Hormesis. Soc. 2018 Sep; 16(3): 155932581878556. Publisher Full Text\n\nLi J, Yao Z-Y, She C, et al.: Effects of low-dose X-ray irradiation on activated macrophages and their possible signal pathways. PLoS One. 2017; 12(10): e0185854. PubMed Abstract | Publisher Full Text\n\nSchröder S, Broese S, Baake J, et al.: Effect of Ionizing Radiation on Human EA.hy926 Endothelial Cells under Inflammatory Conditions and Their Interactions with A549 Tumour Cells. J. Immunol. Res. 2019; 2019: 1–14. Publisher Full Text\n\nPandey R, Shankar BS, Sharma D, et al.: Low dose radiation induced immunomodulation: effect on macrophages and CD8+ T cells. Int. J. Radiat. Biol. 2005 Nov; 81(11): 801–812. PubMed Abstract | Publisher Full Text\n\nPrasanna PG, Woloschak GE, DiCarlo AL, et al.: Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?. Radiat. Res. 2020 Nov 10; 194(5): 452–464. PubMed Abstract | Publisher Full Text\n\nSanmamed N, Alcantara P, Cerezo E, et al.: Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report. Int. J. Radiat. Oncol. Biol. Phys. 2021 Mar 15; 109(4): 880–885. PubMed Abstract | Publisher Full Text\n\nPandey SR: Underlying data. Figshare. Collection. 2021. Publisher Full Text\n\nHess CB, Nasti TH, Dhere VR, et al.: Immunomodulatory Low-Dose Whole-Lung Radiation for Patients with Coronavirus Disease 2019-Related Pneumonia. Int. J. Radiat. Oncol. Biol. Phys. 2021 Mar 15; 109(4): 867–879. PubMed Abstract | Publisher Full Text\n\nAmeri A, Ameri P, Rahnama N, et al.: Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Final Results of a Pilot Study. Int. J. Radiat. Oncol. Biol. Phys. 2021 Mar 15; 109(4): 859–866. PubMed Abstract | Publisher Full Text\n\nDesjardins AU: Radiotherapy for inflammatory conditions. J. Am. Med. Assoc. 1941 Jan 18; 116(3): 225–231. Publisher Full Text\n\nCalabrese EJ, Kozumbo WJ, Kapoor R, et al.: Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 2021 Jul; 160: 125–131. PubMed Abstract | Publisher Full Text\n\nDhawan G, Kapoor R, Dhawan R, et al.: Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS). Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 2020 Jun; 147: 212–216. PubMed Abstract | Publisher Full Text\n\nMöhlenkamp S, Thiele H: Ventilation of COVID-19 patients in intensive care units. Herz. 2020 Jun; 45(4): 329–331. PubMed Abstract | Publisher Full Text\n\nDel Castillo R, Martinez D, Sarria GJ, et al.: Low-dose radiotherapy for COVID-19 pneumonia treatment: case report, procedure, and literature review. Strahlenther Onkol Organ Dtsch Rontgengesellschaft Al. 2020 Dec; 196(12): 1086–1093. PubMed Abstract | Publisher Full Text\n\nBrogna B, Bignardi E, Brogna C, et al.: Typical CT findings of COVID-19 pneumonia in patients presenting with repetitive negative RT-PCR. Radiogr. Lond. Engl. 1995. 2021 May; 27(2): 743–747. Publisher Full Text\n\nHani C, Trieu NH, Saab I, et al.: COVID-19 pneumonia: A review of typical CT findings and differential diagnosis. Diagn. Interv. Imaging. 2020 May; 101(5): 263–268. PubMed Abstract | Publisher Full Text\n\nMarinella MA: Routine antiemetic prophylaxis with dexamethasone during COVID-19: Should oncologists reconsider?. J. Oncol. Pharm. Pract. Off. Publ. Int. Soc. Oncol. Pharm. Pract. 2020 Sep; 26(6): 1482–1485. PubMed Abstract | Publisher Full Text\n\nTasavon Gholamhoseini M, Yazdi-Feyzabadi V, Goudarzi R, et al.: Safety and Efficacy of Remdesivir for the Treatment of COVID-19: A Systematic Review and Meta-Analysis. J. Pharm. Pharm. Sci. Publ. Can. Soc. Pharm. Sci. Soc. Can. Sci. Pharm. 2021; 24: 237–245. Publisher Full Text\n\nLin EC: Radiation Risk From Medical Imaging. Mayo Clin. Proc. 2010 Dec 1; 85(12): 1142–1146. PubMed Abstract | Publisher Full Text\n\nJones JGA, Mills CN, Mogensen MA, et al.: Radiation dose from medical imaging: a primer for emergency physicians. West. J. Emerg. Med. 2012 May; 13(2): 202–210. PubMed Abstract | Publisher Full Text\n\nShah DJ, Sachs RK, Wilson DJ: Radiation-induced cancer: a modern view. Br. J. Radiol. 2012 Dec 1; 85(1020): e1166–e1173. PubMed Abstract | Publisher Full Text\n\nFields TR: Steroid Side Effects: How to Reduce Corticosteroid Side Effects. Hospital for Special Surgery.[cited 2021 Sep 22]. Reference Source\n\nDyer O: Covid-19: India sees record deaths as “black fungus” spreads fear. BMJ. 2021 May 13; 373: n1238. Publisher Full Text\n\nHo KS, Narasimhan B, Difabrizio L, et al.: Impact of corticosteroids in hospitalised COVID-19 patients. BMJ Open Respir. Res. 2021 Apr; 8(1): e000766. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "120350",
"date": "24 Jan 2022",
"name": "Sudeep Acharya",
"expertise": [
"Reviewer Expertise Infectious disease",
"pulmonary disease",
"critical care medicine",
"mechanical ventilation."
],
"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 have a good research question which falls within current literature. They have clearly described the methods of data collection and interpretation. This is a small study and very small population group analysed which might have resulted in underpowered study. Also there were many variables and confounders in those analysed studies which the authors have mentioned in the limitation part. Overall they have done a good job trying to look for an alternative pathway in the treatment of COVID-19 when there is no certain guideline to treat one.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "120357",
"date": "25 Jan 2022",
"name": "Ritesh Neupane",
"expertise": [
"Reviewer Expertise Clinical research in 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\nThe review attempts to look at an interesting modality of treatment possibility for COVID-19 patients: LDRT. The methods are clear and appear rigorously done. It concludes that, despite improvement in inflammatory markers, LDRT cannot be sufficiently supported due to strong confounding factors like use of steroids and other currently approved therapies. The conclusion goes in tandem with the observations, though it is quite underpowered.\nI would recommend authors and co-authors highlight why this review work is different from the paper by Kapoor et al which has evaluated the studies presented in this submitted report.\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": "7841",
"date": "21 Feb 2022",
"name": "Saroj Adhikari Yadav",
"role": "Author Response",
"response": "Thank you for meticulously reviewing this manuscript and providing your review and feedback. Regarding the article you referenced, Kapoor et. al. published an expert opinion in the 'news and views' section giving an expert view about LDRT use for the management of COVID 19. In contrast, this research is a systematic review to evaluate all the clinical and radiological effects of LDRT in patients with SARS due to COVID-19. Thank you for your kind review and suggestions."
}
]
},
{
"id": "120360",
"date": "08 Feb 2022",
"name": "Prashant Gupta",
"expertise": [
"Reviewer Expertise Diagnostic Radiology",
"Radio-interventions",
"Clinical research"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have done a great job to evaluate the role of low-dose radiotherapy in the management of COVID-19 patients. However, the included studies' number is small which has underpowered this review and may have an effect on the conclusion. Methods, analysis, and presentation of data need to be described in a little bit more detail and in a more clarified way. They have well-described about the biases and confounders about the included studies in this review that have caused limitations in the study.\nSpecific recommendations are as follows:\n1. In Table 2, the answers column are not clearly defined for which group.\n2. Much information in Table 3 is not written clearly. I missed the flow in writing.\n3. Data extraction portion could be written more clearly.\n4. In the methods section, eligibility criteria need to be revised too.\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? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-62
|
https://f1000research.com/articles/10-263/v1
|
01 Apr 21
|
{
"type": "Software Tool Article",
"title": "ContactJ: Lipid droplets-mitochondria contacts characterization through fluorescence microscopy and image analysis",
"authors": [
"Gemma Martín",
"Marta Bosch",
"Elisenda Coll",
"Robert G. Parton",
"Albert Pol",
"Maria Calvo",
"Marta Bosch",
"Elisenda Coll",
"Robert G. Parton",
"Albert Pol"
],
"abstract": "Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and together with mitochondria key regulators of cell bioenergetics. LDs communicate with mitochondria and other organelles forming “metabolic synapse” contacts to ensure that lipid supply occurs where and when necessary. Although transmission electron microscopy analysis allows an accurate and precise analysis of contacts, the characterization of a large number of cells and conditions can become a long-term process. In order to extend contact analysis to hundreds of cells and multiple conditions, we have combined confocal fluorescence microscopy with advanced image analysis methods. In this work, we have developed the ImageJ macro script ContactJ, a novel and straight image analysis method to identify and quantify contacts between LD and mitochondria in fluorescence microscopy images allowing the automatic analysis. This image analysis workflow combines colocalization and skeletonization methods, enabling the quantification of LD-mitochondria contacts together with a complete characterization of organelles and cellular parameters. The correlation and normalization of these parameters contribute to the complex description of cell behavior under different experimental energetic states. ContactJ is available here: https://github.com/UB-BioMedMicroscopy/ContactJ/tree/1.0",
"keywords": [
"Contact sites",
"Lipid Droplets",
"Mitochondria",
"Image Processing and Analysis",
"ImageJ",
"Fluorescence Microscopy",
"Bioimaging",
"Interactome"
],
"content": "Introduction\n\nLipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and together with mitochondria key regulators of cell’s bioenergetics. They supply essential lipids to produce signalling molecules, membrane building blocks, and the metabolic energy needed to survive during nutrient poor periods.1\n\nIn order to achieve their functions, LDs communicate with mitochondria and other organelles (endoplasmic reticulum, endosomes, peroxisomes and vacuoles) forming membrane contact sites,2 “metabolic synapses”, to ensure that lipid provision occurs where and when necessary.1,3,4 Contact sites between these organelles have been described and characterized by transmission electron microscopy (TEM) as it resolves at the membrane scale where these contacts take place.2,5 Whereas TEM allows accurate and precise characterization of contacts, their analysis on a large number of cells and conditions can become a long-term process. On the other hand, confocal fluorescence microscopy combined with advanced image analysis methods enable to extend contact analysis to hundreds of cells and multiple conditions.\n\nTypically, in fluorescence microscopy, the contacts between cellular organelles, the organelle interactome, have been studied by colocalization or overlapping regions of the organelles masks6 or measuring the fraction of intensity of other organelles near to LD.7\n\nIn the present work, we describe a novel and straight image analysis method (ContactJ) to identify and quantify contact regions between LD and mitochondria in fluorescence microscopy images allowing the automatic analysis of hundreds of cells and multiple conditions. This image analysis workflow combines colocalization and skeletonization methods, enabling the detection of LD-mitochondria contacts together with a complete characterization of organelles and cellular parameters (morphometry and distribution). The correlation and normalization of these parameters contribute to the complex description of cells response under different experimental conditions such as metabolic or pathogenic states.\n\n\nMethods\n\nSample preparation and imaging have been previously described in detail.4 Briefly, HEK293 cells were grown in fibronectin coated glass coverslips. Cells were fixed for 60 min in 4% paraformaldehyde, permeabilized in 0.15% Triton X-100 for 10 min, followed by blocking with 1% BSA (A7906, Sigma-Aldrich), 0.1% Tween in PBS for 15 min. Labeling was achieved by incubating cells for 1 hour at room temperature with rabbit polyclonal anti-TOM20 (1:500; ab186734, Abcam) diluted in blocking solution. Primary antibody was detected with donkey anti-rabbit IgG AlexaFluor 555 (A321094) from ThermoFisher Scientific, diluted 1:250 in blocking solution. Finally, cells were labeled with DAPI (1: 4000; ThermoFisher) and LDs were stained with BODIPY 493/503 (1:1000; Molecular Probes) for 10min at room temperature, washed twice with PBS and coverslips were mounted with Mowiol (475904; Calbiochem, Merck).\n\nImaging of LDs, mitochondria and nuclei was performed using a LSM880 laser scanning spectral confocal microscope equipped with an AxioObserver Z1 inverted microscope. DAPI, BODIPY 493/503, and Alexa Fluor 555 images were acquired sequentially using 405, 488 and 561 nm lasers, dichroic beam splitters, emission detection ranges of 415-480 nm, 500-550 nm and 571-625 nm, respectively, and the confocal pinhole was set at 1 Airy Unit (AU). Spectral detection was performed using 2 photomultipliers and 1 central GaAsP. Images were acquired in a 1024 × 1024 format, pixel size at 93 × 93 nm, and integration time of 0.51 microseconds. Sample preparation and image acquisition of TEM image from Figure 3a has been previously described in detail.5\n\nWe have developed ContactJ, a macro script for the open-source image analysis software ImageJ.8,9 This macro automatically and rapidly quantifies confocal images that are saved in a folder and returns the database of the resulting measurements, images and Regions of Interests (ROIs) in a “Results” folder. Thus, inexperienced users with no prior image analysis experience will find it easy to use. As can be seen in Figure 1, the flowchart illustrates how the macro automatically detects and measures LD-mitochondria linear contacts by combining standard and machine learning segmentation processes and the novel use of colocalization together with skeletonization methods from a large number of fluorescence images.\n\nLD, Mitochondria, Colocalization Area and final Contact Site are represented in green, red, yellow and black respectively.\n\nFirst, ContactJ macro performs the segmentation of the cell, LD and mitochondria separately. For the segmentation of the cell, channels from mitochondria and LD were intensity compensated and added to a binary mask from nuclei. The resulting image was used to find local maxima (with prominence of 100) and to obtain subsequently the segmented particles binary image. Segmented particles limits were encoded as 0 value on the binarized image from the three merged channels. Limits between cells allowed to accurately segment, individualize and store cells as ROIs (see Figure 2a). LD segmentation was achieved through a Trainable Weka Segmentation classifier10 on LD channel image (see Figure 2b) and mitochondria were segmented by intensity thresholding (autothreshold method “Otsu”) (see Figure 2c).\n\nHek293 cells were labelled with anti TOM20 antibody (mitochondria) in red, Bodipy493/505 (LDs) in green and DAPI (nuclei) in blue. The different regions of interest resulting from segmentation are highlighted in white (a) Cell Segmentation, (b) LD segmentation, (c) mitochondria segmentation and (d) LD-mitochondria contacts. Insert in d) shows a detail of how contact regions found by ContactJ are accurate and individualized per LD.\n\nOn one hand, contact regions between mitochondria and LD were first obtained using the Colocalization plugin.11 This plugin highlights the colocalized “contact” points between mitochondria and LD 8-bits images (or stacks). The plugin generates an 8 bit binary image with only the colocalized points (Display value = 255). Two points are considered as colocalized if their respective intensities are strictly higher than the threshold of their channels (autothreshold methods “Yen” for LD channel and “Otsu” for mitochondria channel), and if their ratio (of intensity) is strictly higher than the ratio setting value (set to 50%: ratio (0-100%)). On the other hand, the regions of individualized LD are obtained using the Find Maxima tool with Segmented particles result from the LD mask. Finally, individualized contact regions were converted to a contour line section by performing the skeletonization of the minimum image calculation from the colocalization mask and the segmented particles result from LD. Contact perimeter and contact counts (a contact is defined as a continuous contact line) were quantified, obtaining the linear LD-mitochondria contact of each cell (see Figure 2d).\n\nFinally, along the execution of the macro, all the data is stored in arrays (cell, LD and mitochondria areas and perimeters, contact perimeter, number of contacts, etc). Moreover, this data is stored in a.txt database file allowing the traceability of the results for each cell and each image.\n\nImageJ/Fiji with the Colocalization11 and WEKA10 plugins should be installed and ContactJ run from ImageJ macro editor. The software can be tested with the sample data provided (in Underlying data12). First, the user should prepare a set of images and organize them into a folder. In this images folder the user should create a subfolder named “Model” with the data and model files obtained specifically for the segmentation of LD channel using the machine learning WEKA plugin. Once ContactJ runs, macro asks to the user the folder to analyse. Automatically, ContactJ opens the images one by one analysing them, cell by cell, and saving ROIs and all the measurements data obtained (areas, intensity, contact, perimeter …) in a .txt file as a data base.\n\n\nUse cases\n\nContactJ has been developed and tested for the contact analysis of hundreds of HEK293 cells treated or untreated with lipopolysaccharide (LPS) and expressing or not a protein of interest PLIN5.4\n\nTaking advantage of fluorescence multilabelling, the cells have been segmented and all parameters can be expressed per cell individually. The macro segments the nucleus, LDs and mitochondria from each cell and it obtains the following parameters that are stored in a data base table: Cell Area, number of LDs and Mitochondria, LDs and Mitochondria Total Area, Mean LD Area per cell, Standard deviation of the LD mean Area, Mean LD Perimeter and Total Mitochondria and LD Perimeter\n\nThe main novelty and distinctive feature from ContactJ is that it creates a contact line corresponding to each contact site between mitochondrion and LD. In order to obtain the contact site, ContactJ first generates a colocalization region corresponding to the overlapping fluorescence from both organelles, using the Colocalization plugin. Then, this shape is skeletonized generating a line of equidistant points to its boundaries representing the contact site. The macro stores in the data base file also the total length of the contact sites, the mean length of each contact and the number of contacts detected per cell. In the mentioned work, the results were expressed as Total Contact Length/Cell and compared between cell populations and treatments.4\n\n\nDiscussion\n\nOne of the innovative and distinctive features of ContactJ is that it creates a linear contact region on the mid plane of the LD in close proximity to Mitochondrion, representing the most probable contact site between both organelles.\n\nAlthough light microscopy resolution limit prevents assertion of true interaction, the analysis of inter organelle contacts by fluorescence microscopy is accepted as an indicator of possible communication between these two organelles, bringing many advantages when performing contact analysis at a high scale of samples and conditions. TEM is used to measure contacts between organelles as it resolves at the membrane scale where these contacts take place, as can be seen in Figure 3(a). ContactJ measurements of contact perimeter between LD and mitochondria are 2-3 times bigger compared to TEM measurements4 (Figure 3). The main reasons for this difference are, first, that 2D confocal microscopy image represents a projection of approximately 500nm sample thickness, compared to the 70nm of the ultra-thin TEM lamella and consequently, it is collecting a higher proportion of membrane and contacts. Secondly, the intrinsic difference in resolution would affect more directly the measurements of small contacts by light microscopy overestimating them. Therefore, the contacts obtained with ContactJ can be considered reliable compared to those observed by TEM.\n\nObtaining contact regions, together with multiple morphological parameters of organelles, allows the calculation of descriptive statistics that would help describing cellular response. In front a metabolic or pathogenic event, cells need to regulate the transfer and communication between organelles. Among many possible cell reactions, they may change the contact surface between organelles together with the organelle size, number and distribution. For example, in this case, the quantification with Contact J of the contact length and the LD perimeter would allow the calculation of the LD-Mitochondria “transfer or communication” efficiency for each cell (Contact length/LD Perimeter Length) helping in the comparison between cells response.\n\nIn conclusion, the described image analysis workflow unveils a wide range of possibilities in the automatic quantification of LD and mitochondria contacts and it also has been tested, and it is applicable, to the study of other organelles in 2D and 3D images. Obtaining contact regions together with multiple cell and organelles parameters allow building descriptive statistics of the cells response. Moreover, its application in a large number of images enables the use of High Content Screening and Analysis, highly increasing the quality and statistical confidence of the results.\n\n\nData availability\n\nZenodo: UB-BioMedMicroscopy/ContactJ: ContactJ, http://doi.org/10.5281/zenodo.456993512\n\nThis project contains the trained model and data for Weka plugin and example images.\n\n\nSoftware availability\n\nSource code available from: https://github.com/UB-BioMedMicroscopy/ContactJ/tree/1.0\n\nArchived source code as at time of publication: http://doi.org/10.5281/zenodo.456993512\n\nLicense: CC0",
"appendix": "Acknowledgements\n\nThis publication was supported by COST Action NEUBIAS (CA15124), funded by COST (European Cooperation in Science and Technology).\n\nWe acknowledge NEUBIAS Cost Action NEUBIAS - COST ActionCA15124 www.neubias.org for Image Analysis courses, tutorials and repositories and their important task in training Image Analysts.\n\nData presented in this work is part of the published article.4\n\nThis paper is dedicated to the living memory of Anna Bosch.\n\n\nReferences\n\nBosch M, Parton RG, Pol A: Lipid Droplets, Bioenergetic Fluxes, and Metabolic Flexibility. Semin Cell Dev Biol. Elsevier Ltd; December 2020; 33–46. PubMed Abstract | Publisher Full Text\n\nParton RG, Bosch M, Steiner B, et al.: Novel Contact Sites between Lipid Droplets, Early Endosomes, and the Endoplasmic Reticulum. J Lipid Res. American Society for Biochemistry and Molecular Biology Inc; November 1, 2020; p 1364. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchuldiner M, Bohnert M: A Different Kind of Love – Lipid Droplet Contact Sites. Biochim Biophys Acta Mol Cell Biol Lipids. Elsevier B.V; October 2017; 1188–1196. PubMed Abstract | Publisher Full Text\n\nBosch M, Sánchez-Álvarez M, Fajardo A, et al.: Mammalian Lipid Droplets Are Innate Immune Hubs Integrating Cell Metabolism and Host Defense. Science (80-.). 2020; 370(6514). PubMed Abstract | Publisher Full Text\n\nHerms A, Bosch M, Reddy BJN, et al.: Activation Promotes Lipid Droplet Dispersion on Detyrosinated Microtubules to Increase Mitochondrial Fatty Acid Oxidation. Nat. Commun. 2015; 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nValm AM, Cohen S, Legant WR, et al.: Applying Systems-Level Spectral Imaging and Analysis to Reveal the Organelle Interactome. Nature. Nature Publishing Group; June 1, 2017; 162–167. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFreyre CAC, Rauher PC, Ejsing CS, et al.: MIGA2 Links Mitochondria, the ER, and Lipid Droplets and Promotes De Novo Lipogenesis in Adipocytes. Mol. Cell. 2019; 76: 811–825. e14. PubMed Abstract | Publisher Full Text\n\nSchindelin J, Arganda-Carreras I, Frise E, et al.: Fiji: An Open-Source Platform for Biological-Image Analysis. Nat Methods. July 2012; 676–682. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchneider CA, Rasband WS, Eliceiri KW: NIH Image to ImageJ: 25 Years of Image Analysis. Nat Methods. July 2012; 671–675. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArganda-Carreras I, Kaynig V, Rueden C, et al.: Trainable Weka Segmentation: A Machine Learning Tool for Microscopy Pixel Classification. Bioinformatics. 2017; 33(15): 2424–2426. PubMed Abstract | Publisher Full Text\n\nPierre Bourdoncle (Institut Jacques Monod, Service Imagerie, P: Colocalization Plugin.Reference Source\n\nMariaCalvo: UB-BioMedMicroscopy/ContactJ: ContactJ (Version 1.0). Zenodo. 2021, March 1. Publisher Full Text"
}
|
[
{
"id": "82672",
"date": "22 Apr 2021",
"name": "Mafalda Sousa",
"expertise": [
"Reviewer Expertise Light microscopy image analysis specialist. 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\nA novel ImageJ macro script called ContactJ that allows for the automatic determination of contacts formed between lipid droplets (LD) and mitochondria in cells is presented. An interaction that is usually assessed by electron microscopy, involving a reduced number of biological events analyzed, is assessed in this work by the combination of fluorescence microscopy with automatic image analysis. This approach boosts the number of biological events analyzed. It turns the analysis more time-efficient by using colocalization methods combined with the segmentation of the LD, which extracts the contact region on the midplane of the LD that is in close proximity of mitochondria.\nThe limitation of using light microscopy to look at very small contacts is clearly stated. Nevertheless, the use of this imaging technique as an indicator of possible contact between different organelles is well accepted in the community. Light microscopy was already shown to provide more information about the contacts between LD and mitochondria due to the sample thickness that is bigger than the sample prepared for transmission electron microscopy.\nContactJ is presented as a well-established workflow. The authors combine tools previously developed in an exquisite way, such as the trainable Weka segmentation classifier and the colocalization plugin, with the conventional object segmentation. Figure 1 is very self-explanatory of the workflow followed by the macro script. Another positive aspect is the detailed output of the macro script that allows for a complex and quantitative analysis of the contacts established between the LD and mitochondria. The Operation section description is well written, and no problems were found while running the macro script; it is a very simple and straightforward process.\nDespite the positive aspects mentioned above, there are fewer positive points that need to be checked:\nRegarding the strategy applied for the segmentation of the cells (page 3), most probably extra cell labeling could be used to facilitate this step. Usually, the staining of a cytoskeleton protein or the cell membrane staining is used to define the cells' boundary facilitating the cell segmentation step. The authors may consider such an approach in the sample preparation and imaging.\nNot so thorough is the description of the code behind the workflow. The authors are sparse in describing the different steps that make up the workflow. Some of those steps are not even mentioned in the Implementation section of the manuscript, being only perceptible by reading or running the code line by line, which jeopardizes reproducibility. Likewise, the comments along the macro script are also sparse. A more detailed and extensive workflow description is needed, both in the manuscript and in the macro script. ImageJ good code practices suggest that you mention the ImageJ version and cite it in the associated publication.\nThe citation \"channels from mitochondria and LD were intensity compensated\" should be explained to be more explicit. The authors commented in the script (line 143) \"calculate addition 0.2LD+0.2mitochondria\", meaning that the intensity compensation was 20% of the original values. Is there a reason for assigning this value? Should it be considered as a variable dependent on the dataset?\nIn the Implementation section (page 4), it is stated that “the colocalized \"contact\" points between the mitochondria and LD 8-bit images (or stacks)\". It is not clear if an 8-bit image is mandatory for determining the contact points or the number of channels that may compose the image. These details should be clearly stated. Additionally, as the reference to use a stack of images is made, the dataset available to test the macro script should contain this type of image.\nThe available dataset for testing the code is unfortunately diminished. Only two very similar images are available for testing the script. The dataset for testing this tool should be bigger and the images must represent a real, heterogeneous population of cells to test the proposed script’s execution and performance.\nFollowing the same lines, the script should be tested for quality and performance and presented in the manuscript. A previous publication shows the analysis of hundreds of HEK293 cells by the application of ContactJ. However, a comparison between the ContactJ results and another analysis method (such as manual quantification or using proprietary software) is not presented. Moreover, the usage of ContactJ to look at LD-mitochondria contacts in different cells (primary cells such as neurons, or other cell lines such as PC12 or CAD cells) could be included. Such validation is of extreme importance to show robustness and accuracy on the data obtained by the application of ContactJ.\nThroughout the manuscript, the term database refers to the script output .txt file created upon the analysis (page 5). In our understanding, this terminology is incorrectly used since a database is a set of related tables. The authors can use the term table since the output is indeed a table.\nLooking closer to the presented macro in ImageJ, some adjustments should be made. Along with the code, several hard-coded values are used, such as thresholding values and filter parameters. It is unclear how these values may be applied in different images or conditions. Maybe the authors should consider building a graphical user interface for prompting these parameters. Plus, there is no code error handling, not testing, for example, if the input is an 8-bit image with 3 channels. The algorithm premises that images are 8-bit depth, although this is not mentioned nor guaranteed along with the code.\nThere is likely an error in the option of removing cell ROIs (lines 180-190). When deleting the cells, the results table with cell measurements is not updated and the deleted ROIs are the last ones on the table and not the ones corresponding to the correct position in the image. This error affects the results obtained, so it should be corrected. Furthermore, the Resulting txt file needs to be truncated or deleted from the results folder. Otherwise, it will append the results of further analysis.\nRunning the ContactJ macro script takes some time (this should also be measured). The authors could improve the code performance by reducing the number of for-cycles and by closing the images while the code is running (not only at the end). Also, the analysis could be set in batch mode (true), showing only the images for quality control.\nWhile ContactJ is being presented as a tool to look for contacts between LD and mitochondria, the translational application of this script is not obvious. It might strengthen the work if more broad applicability of the ContactJ is mentioned or, at least, speculated. We see the potential for the application of ContactJ on image analysis where interaction between different cell types (oligodendrocytes-neuron interaction, microglia-neuron interaction, yeast-macrophage interaction.), or between different cellular organelles is done. May the authors comment on these possible applications and add them to the Discussion section?\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? No\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? Partly",
"responses": [
{
"c_id": "7654",
"date": "18 Jan 2022",
"name": "Maria Calvo",
"role": "Author Response",
"response": "A novel ImageJ macro script called ContactJ that allows for the automatic determination of contacts formed between lipid droplets (LD) and mitochondria in cells is presented. An interaction that is usually assessed by electron microscopy, involving a reduced number of biological events analyzed, is assessed in this work by the combination of fluorescence microscopy with automatic image analysis. This approach boosts the number of biological events analyzed. It turns the analysis more time-efficient by using colocalization methods combined with the segmentation of the LD, which extracts the contact region on the midplane of the LD that is in close proximity of mitochondria. The limitation of using light microscopy to look at very small contacts is clearly stated. Nevertheless, the use of this imaging technique as an indicator of possible contact between different organelles is well accepted in the community. Light microscopy was already shown to provide more information about the contacts between LD and mitochondria due to the sample thickness that is bigger than the sample prepared for transmission electron microscopy. ContactJ is presented as a well-established workflow. The authors combine tools previously developed in an exquisite way, such as the trainable Weka segmentation classifier and the colocalization plugin, with the conventional object segmentation. Figure 1 is very self-explanatory of the workflow followed by the macro script. Another positive aspect is the detailed output of the macro script that allows for a complex and quantitative analysis of the contacts established between the LD and mitochondria. The Operation section description is well written, and no problems were found while running the macro script; it is a very simple and straightforward process. Despite the positive aspects mentioned above, there are fewer positive points that need to be checked: Thank you for reviewing the article and pointing out the issues that would help to improve the presented work. We have tried to address all the suggestions and criticisms. 1) Regarding the strategy applied for the segmentation of the cells (page 3), most probably extra cell labelling could be used to facilitate this step. Usually, the staining of a cytoskeleton protein or the cell membrane staining is used to define the cells' boundary facilitating the cell segmentation step. The authors may consider such an approach in the sample preparation and imaging. The cell segmentation has been adapted to a specific sample and experimental conditions that didn’t support any cell mask or cytoskeleton labelling. To clarify this point, we have added a comment in the methods section that whenever is possible it is recommended to add a fourth channel of cytoskeleton, membrane or cell labelling to facilitate the cell segmentation step. Changes in the manuscript: “The present work has been adapted to the particular conditions of this experiment dataset where membrane or cell mask labelling couldn’t be implemented. For this reason, a smart strategy for the cell segmentation has been used: the addition of the available cytoplasmic labellings (LD plus Mitochondria) and the Nucleus staining to define the cell region. Whenever it is possible, it is recommended to use a cell mask labelling to facilitate cell segmentation and individualization. In such case, the workflow for cell segmentation should be modified.” 2) Not so thorough is the description of the code behind the workflow. The authors are sparse in describing the different steps that make up the workflow. Some of those steps are not even mentioned in the Implementation section of the manuscript, being only perceptible by reading or running the code line by line, which jeopardizes reproducibility. Likewise, the comments along the macro script are also sparse. A more detailed and extensive workflow description is needed, both in the manuscript and in the macro script. ImageJ good code practices suggest that you mention the ImageJ version and cite it in the associated publication. We have added a more detailed and extensive workflow description and the ImageJ version both in the manuscript and in the macro script. 3) The citation \"channels from mitochondria and LD were intensity compensated\" should be explained to be more explicit. The authors commented in the script (line 143) \"calculate addition 0.2LD+0.2mitochondria\", meaning that the intensity compensation was 20% of the original values. Is there a reason for assigning this value? Should it be considered as a variable dependent on the dataset? As previously explained, the cell segmentation was adapted to the particular conditions of this experiment dataset where membrane or cell mask labelling couldn’t be implemented. In this case, a practical strategy was to use the addition of the available cytoplasmic labelling (LD plus Mitochondria) and the Nucleus staining to define the cell region. In such particular case, in order to have similar intensity contributions from cytoplasmic labelling and nucleus, LD and mitochondria channels were multiplied by 0.2 to reduce its intensity contribution and make it more similar to the nucleus intensity. As pointed by the reviewers this value is dependent on the dataset and we have included a GUI to change this and other dataset dependent parameters. Changes in the manuscript: “First, ContactJ macro performs the segmentation of the cells, LD and mitochondria separately. For the segmentation of the cell, channels from mitochondria and LD were intensity compensated and added to a binary mask from nuclei. Cell segmentation was adapted to the particular conditions of this experiment dataset where a membrane or a cell mask labelling couldn’t be implemented. Briefly, cell segmentation was achieved by adding the available cytoplasmic labellings (LD plus Mitochondria) and the Nucleus staining. To obtain similar intensity contributions from cytoplasmic labelling and nucleus, LD and mitochondria channels were multiplied each by 0.2 to reduce its intensity contribution and make it more similar to the nucleus intensity. As these factors are dependent on the different experimental conditions, they can be modified at the graphical user interface (GUI) at the beginning of the macro (referred at the GUI as Compensation). Intensity compensated channels from mitochondria and LD were added to a binary mask from nuclei.” 4) In the Implementation section (page 4), it is stated that “the colocalized \"contact\" points between the mitochondria and LD 8-bit images (or stacks)\". It is not clear if an 8-bit image is mandatory for determining the contact points or the number of channels that may compose the image. These details should be clearly stated. Additionally, as the reference to use a stack of images is made, the dataset available to test the macro script should contain this type of image. As suggested by the referees, a more detailed description of the input image requirements has been included in the manuscript and the macro script. Changes in the manuscript: “This macro automatically and rapidly quantifies confocal images (1 section, 8-12-16 bit depth)” In reference to the stack images option, there is no limitation to implement the analysis through 3D stacks or time series, however the direct purpose of this macro was the analysis of 2D images to extend contact analysis to hundreds of cells and multiple conditions. As mentioned along the work, contact analysis can be extended in any image type i.e. 3D images or through time. To facilitate this, we provide, at github, the core code of ContactJ (ContactJ4All) that generates a contacts mask from two channels from 2D images or from stacks (3D or time series). By combining the core ContactJ code with 3D objects analysis or objects tracking, contact analysis can be extended in 3D or time series. Changes in the manuscript: “ContactJ application can be extended to the contact analysis between other organelles, in 2D, 3D or time series. In fact, this code has been already adapted for the contact tracking analysis between LD and Endoplasmic Reticulum in time lapse experiments (13). To facilitate the applicability of ContactJ in 3D or time series images, and its combination with any available 3D objects analysis or objects tracking methods, respectively, a straightforward core code of ContactJ (ContactJ4All) has been developed. This code is ready to be included in any workflow and available on github https://zenodo.org/badge/latestdoi/442839907 . Also, an example dataset from xyz and xyt images is included to test its performance.” 5) The available dataset for testing the code is unfortunately diminished. Only two very similar images are available for testing the script. The dataset for testing this tool should be bigger and the images must represent a real, heterogeneous population of cells to test the proposed script’s execution and performance. To test the script performance and reproducibility, the dataset has been increased with more images representing a heterogeneous population of cells. 6) Following the same lines, the script should be tested for quality and performance and presented in the manuscript. A previous publication shows the analysis of hundreds of HEK293 cells by the application of ContactJ. However, a comparison between the ContactJ results and another analysis method (such as manual quantification or using proprietary software) is not presented. Moreover, the usage of ContactJ to look at LD-mitochondria contacts in different cells (primary cells such as neurons, or other cell lines such as PC12 or CAD cells) could be included. Such validation is of extreme importance to show robustness and accuracy on the data obtained by the application of ContactJ. As suggested by the referee, a comparison between the ContactJ results and manual quantification has been performed. The comparison between ContactJ analysis vs Manual analysis shows that although both methods correlate, manual analysis-increases significantly standard deviation reducing reproducibility of the method and overestimating contact length. Additionally, while comparing both methods we have experienced that manual quantification doesn’t allow precise contact tracing around organelles, secondly, that it’s difficult to stablish visual criteria of proximity and finally, that manual tracing is not only time consuming but, after defining tens of contacts per cell, it results in quick user fatigue and loss of detection and precision. All these results reinforce the idea that ContactJ is an objective and reproducible method valid to define and quantify contacts between organelles automatically.” Furthermore, robustness of ContactJ has been tested and validated also in contact analysis between Endoplasmic Reticulum and Lipid Droplets in U2OS cells in live cell imaging experiments https://doi.org/10.1083/jcb.202105060). Changes in the manuscript: “In order to test quality and performance of ContactJ, a comparison between contact manual tracing analysis compared to ContactJ analysis has been performed on 20 cells. Mean and Standard Deviation (microns) from total contact length from Manual quantification were: 44.9220 and 30.1140, respectively, and from ContactJ analysis were: 30.8055 and 18.30792, respectively. ANOVA test was performed and showed no significant difference between both groups means (F=3.209 and p= 0.08) B). Correlation Analysis of the values obtained with both methods showed a correlation index of 0.899 significant at the 0.01 level (see extended data Manual_vs_ContactJ_methods.pdf). The comparison between ContactJ analysis vs Manual analysis shows that although both methods correlate, manual analysis-increases significantly standard deviation reducing reproducibility of the method and overestimating contact length. Additionally, while comparing both methods we have experienced that manual quantification doesn’t allow precise contact tracing around organelles, secondly, that it’s difficult to stablish visual criteria of proximity and finally, that manual tracing is not only time consuming but, after defining tens of contacts per cell, it results in quick user fatigue and loss of detection and precision. All these results reinforce the idea that ContactJ is an objective and reproducible method valid to define and quantify contacts between organelles automatically.” 7) Throughout the manuscript, the term database refers to the script output .txt file created upon the analysis (page 5). In our understanding, this terminology is incorrectly used since a database is a set of related tables. The authors can use the term table since the output is indeed a table. We totally agree that the term database should be substituted by the term table. It has been corrected in the manuscript. Changes in the manuscript: “...that are saved in a folder and returns the table of the resulting measurements, images and Regions of Interests (ROIs) in a “Results” folder.” 8) Looking closer to the presented macro in ImageJ, some adjustments should be made. Along with the code, several hard-coded values are used, such as thresholding values and filter parameters. It is unclear how these values may be applied in different images or conditions. Maybe the authors should consider building a graphical user interface for prompting these parameters. Plus, there is no code error handling, not testing, for example, if the input is an 8-bit image with 3 channels. The algorithm premises that images are 8-bit depth, although this is not mentioned nor guaranteed along with the code. An initial GUI has been implemented to define the dataset dependent parameters (thresholds, ratio…). A more accurate description of the input image requirements has been included (bit depth, channels…) in the manuscript and the macro script. 9) There is likely an error in the option of removing cell ROIs (lines 180-190). When deleting the cells, the results table with cell measurements is not updated and the deleted ROIs are the last ones on the table and not the ones corresponding to the correct position in the image. This error affects the results obtained, so it should be corrected. Furthermore, the Resulting txt file needs to be truncated or deleted from the results folder. Otherwise, it will append the results of further analysis. The reported error has been fixed and now the deleted ROIs results are properly removed from the generated results table. 10) Running the ContactJ macro script takes some time (this should also be measured). The authors could improve the code performance by reducing the number of for-cycles and by closing the images while the code is running (not only at the end). Also, the analysis could be set in batch mode (true), showing only the images for quality control. The code has been reviewed to avoid redundant operations. Images now, are being closed when not necessary to improve the code’s performance. In addition, the analysis has been set in batch mode. 11) While ContactJ is being presented as a tool to look for contacts between LD and mitochondria, the translational application of this script is not obvious. It might strengthen the work if more broad applicability of the ContactJ is mentioned or, at least, speculated. We see the potential for the application of ContactJ on image analysis where interaction between different cell types (oligodendrocytes-neuron interaction, microglia-neuron interaction, yeast-macrophage interaction.), or between different cellular organelles is done. May the authors comment on these possible applications and add them to the Discussion section? The translational application of ContactJ is clear in the context of the lipid droplets role because their interaction with other organelles are now recognized as key factors in physiological and disease processes. As suggested by the referees we have commented the translational aspect of the macro and its possible applications in the discussion. We appreciate the referees view of ContactJ ‘s potential. In fact, this code has already been extended to the contact analysis between LD and Endoplasmic Reticulum in time lapse experiments (A. Lu et al. J. Cell Biol. 2021 Vol. 221 No. 2 e202105060 https://doi.org/10.1083/jcb.202105060). To facilitate the applicability of ContactJ in 3D or time series images, and its combination with any available 3D objects analysis or objects tracking methods, respectively, we have developed a straightforward core code of ContactJ (ContactJ4all). This code is ready to be included in any workflow and available on github. Also, an example dataset from xyz and xyt images is included to test its performance https://zenodo.org/badge/latestdoi/442839907"
}
]
},
{
"id": "82670",
"date": "24 May 2021",
"name": "Gadea Mata Martinez",
"expertise": [
"Reviewer Expertise Light microscopy image analyst and computer scientist",
"field of artificial intelligence"
],
"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 ContactJ, an ImageJ macro, to identify and quantify contacts between lipid droplets (LD) and mitochondria.\nThis type of analysis is usually performed using electron microscopy. The authors have found a way to carry out a similar study (taking into account the limitations of resolution) using confocal microscopy images.\nThe use of this type of image along with the combination of different analytical techniques and machine learning make this macro an interesting and novel work.\nThe authors clearly describe the workflow of the macro. I would like to highlight the effort that has been put into establishing a clear distinction between each part of it, which helps to monitor and check the results at all times. The figures shown are very clear and leave no room for doubt. Another strength of this work is that this macro has already been used to analyse the work done in a publication.\nHowever, I want to comment on some minor aspects that could be subject to improvement:\nNote that the link in reference 11 is broken. Please replace with: https://imagej.nih.gov/ij/plugins/colocalization.html\nIn the Implementation section, the macro configuration is clearly defined and the parameters that have been used in each step are well described. However, the type of machine learning algorithm used for the LD segmentation is missing.\nIn the Discussion section, it is mentioned that the study can be carried out for 3D images. Adding an example of this type in the test images file is recommended.\nIn this same section, the authors mention that this macro can be used to analyse a large number of images (High Content Screening and Analysis). For this type of analysis, it would be helpful that the option to check if the cells are well-segmented could be activated or deactivated. This way, it could be used to check some images and then run the macro over the entire experiment unsupervised.\nThe macro is fast, and its code is well commented, which makes it easy to read and understand. Considering the different domains that a single type of image may have (such as changes in the intensity of the sample or noise), I suggest that the configuration parameters of the different methods become variables that are described at the beginning of the macro. Therefore, the macro gives the user the possibility, if needed, to quickly and easily change the parameters, avoiding changes within the code.\nSimilarly, in addition to converting the channels used each time into a variable, it is recommended to comment on the code and refer to the channels not only by their colour but also by what they contain, as sometimes the experts use different criteria for the colour that each channel represents.\nAs the macro progresses, the user can watch how several images are opened, which represent the intermediate steps. This intermediate image display slows down the macro, and it is suggested to use the “setBatchMode (true)” option whenever possible to avoid this effect.\nIn addition, it is observed that the intermediate images that have been generated in the different steps remain open until the final result is obtained. To improve the performance of the macro, it is recommended that they are automatically closed when they are no longer needed.\nRegarding the use of GitHub to upload the macro, I recommend that the authors complete the README section, providing information on the installation of the macro, the requirements that are needed for the correct functioning of the macro, and a brief description of its use.\nThe macro gives a robust set of results, which offer the possibility of obtaining interesting relationships, as the authors have commented. However, I recommend adding the calculation of the standard deviation for both the mean of the perimeter of the LD and the mean of the length of the Contact. Since both means are already calculated, it is convenient to calculate the standard deviations for each one.\nAll this would improve and facilitate the use of this macro by others in a general, simple and clear way.\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? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "7655",
"date": "18 Jan 2022",
"name": "Maria Calvo",
"role": "Author Response",
"response": "The authors present ContactJ, an ImageJ macro, to identify and quantify contacts between lipid droplets (LD) and mitochondria. This type of analysis is usually performed using electron microscopy. The authors have found a way to carry out a similar study (taking into account the limitations of resolution) using confocal microscopy images. The use of this type of image along with the combination of different analytical techniques and machine learning make this macro an interesting and novel work. The authors clearly describe the workflow of the macro. I would like to highlight the effort that has been put into establishing a clear distinction between each part of it, which helps to monitor and check the results at all times. The figures shown are very clear and leave no room for doubt. Another strength of this work is that this macro has already been used to analyse the work done in a publication. However, I want to comment on some minor aspects that could be subject to improvement: Thank you for reviewing the article and pointing out the issues that would help to improve the presented work. We have tried to address all the suggestions and criticisms. 1) Note that the link in reference 11 is broken. Please replace with: https://imagej.nih.gov/ij/plugins/colocalization.html Thank you for the clarification, we have corrected it. After the review we have noticed that this plugin is not stable in new FIJI versions. In order to avoid it we have added the code that allows to obtain the colocalization mask (based from the reference Bourdoncle https://imagej.nih.gov/ij/plugins/colocalization.html). This specific code was previously adapted to analyse colocalization with no restrictions of bit depth and for stacks (Vidal-Quadras et al. Traffic. 2011 Dec;12(12):1879-96. doi: 10.1111/j.1600-0854.2011.01274.x. Epub 2011 Sep 21.) 2) In the Implementation section, the macro configuration is clearly defined and the parameters that have been used in each step are well described. However, the type of machine learning algorithm used for the LD segmentation is missing. In agreement with the referee, the information about the Machine Learning algorithms used for LD segmentation is provided and included in the manuscript (methods section). Changes in the manuscript: “LD segmentation was achieved through a Trainable Weka Segmentation classifier on LD channel image (see Figure 2b)) using the classification algorithm Fast Random Forest and the following Training features: Gaussian Blur, Hessian, Membrane projections, Sobel filtre, Difference of Gaussians. Mitochondria were segmented by intensity thresholding (autothreshold method “Otsu”) 3) In the Discussion section, it is mentioned that the study can be carried out for 3D images. Adding an example of this type in the test images file is recommended. As mentioned throughout the work, contact analysis with ContactJ can be adapted to any image type i.e. 3D images (xyz) or through time (xyt). However, the direct purpose of this macro is the analysis of hundreds of cells and multiple conditions from 2D images and therefore it has been optimized for this type of images. As suggested by the referees, in order to adapt contact analysis to any 3D objects analysis or objects tracking methods, we have developed a new multi image ContactJ code that generates a contacts mask from two channels from images either 2D or from stacks (3D or time series). This code is available at github, open to all kind of projects and ready to be included in any code workflow. Also an example dataset from xyz and xyt images is included (https://zenodo.org/badge/latestdoi/442839907). 4) In this same section, the authors mention that this macro can be used to analyse a large number of images (High Content Screening and Analysis). For this type of analysis, it would be helpful that the option to check if the cells are well-segmented could be activated or deactivated. This way, it could be used to check some images and then run the macro over the entire experiment unsupervised. We agree that this option will be helpful for checking performance of the macro and it has been included at the GUI at the beginning of the macro. 5) The macro is fast, and its code is well commented, which makes it easy to read and understand. Considering the different domains that a single type of image may have (such as changes in the intensity of the sample or noise), I suggest that the configuration parameters of the different methods become variables that are described at the beginning of the macro. Therefore, the macro gives the user the possibility, if needed, to quickly and easily change the parameters, avoiding changes within the code. This option can be selected at GUI at the beginning of the macro. As suggested by the referees, an initial GUI has been implemented to define the image dependent variables (thresholds, ratio…). 6) Similarly, in addition to converting the channels used each time into a variable, it is recommended to comment on the code and refer to the channels not only by their colour but also by what they contain, as sometimes the experts use different criteria for the colour that each channel represents. We agree that referring to the channels by what they represent will be more self-explanatory. 7) As the macro progresses, the user can watch how several images are opened, which represent the intermediate steps. This intermediate image display slows down the macro, and it is suggested to use the “setBatchMode (true)” option whenever possible to avoid this effect. We totally agree that setting the macro to Batch Mode will fasten its performance, therefore we have set it. 8) In addition, it is observed that the intermediate images that have been generated in the different steps remain open until the final result is obtained. To improve the performance of the macro, it is recommended that they are automatically closed when they are no longer needed. To improve the code’s performance, now images are being closed when not necessary. 9) Regarding the use of GitHub to upload the macro, I recommend that the authors complete the README section, providing information on the installation of the macro, the requirements that are needed for the correct functioning of the macro, and a brief description of its use. We have provided the requested information in the Readme section of GitHub. 10) The macro gives a robust set of results, which offer the possibility of obtaining interesting relationships, as the authors have commented. However, I recommend adding the calculation of the standard deviation for both the mean of the perimeter of the LD and the mean of the length of the Contact. Since both means are already calculated, it is convenient to calculate the standard deviations for each one. All this would improve and facilitate the use of this macro by others in a general, simple and clear way. We totally agree that this data was missing and its inclusion improves the obtained information."
}
]
}
] | 1
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https://f1000research.com/articles/10-263
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https://f1000research.com/articles/10-535/v1
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05 Jul 21
|
{
"type": "Study Protocol",
"title": "Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: a scoping review protocol",
"authors": [
"Emmanuel Firima",
"Lucia Gonzalez",
"Jacqueline Huber",
"Jennifer M. Belus",
"Fabian Raeber",
"Ravi Gupta",
"Joalane Mokhohlane",
"Madavida Mphunyane",
"Alain Amstutz",
"Niklaus Daniel Labhardt",
"Lucia Gonzalez",
"Jacqueline Huber",
"Jennifer M. Belus",
"Fabian Raeber",
"Ravi Gupta",
"Joalane Mokhohlane",
"Madavida Mphunyane",
"Alain Amstutz",
"Niklaus Daniel Labhardt"
],
"abstract": "Background: The burden of type 2 diabetes mellitus (T2DM) is increasing in low- and middle-income countries, including sub-Sahara Africa (SSA). However, awareness of and access to T2DM diagnosis and care remain low in SSA, leading to delayed treatment, early morbidity, and mortality. Particularly in rural settings with long distances to health care facilities, community-based care models may contribute to increased timely diagnosis and care. This scoping review aims to summarize and categorize existing models of community-based care for T2DM among non-pregnant adults in SSA, and to synthesize the evidence on acceptance, clinical outcomes, and engagement in care. Method and analysis: This review will follow the framework suggested by Arskey and O’Malley, which has been further refined by Levac et al. and the Joanna Briggs Institute. Electronic searches will be performed in Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus, supplemented with backward and forward citation searches. We will include cohort studies, randomized trials and case-control studies that report cases of non-pregnant individuals diagnosed with T2DM in SSA who receive a substantial part of care in the community. Our outcomes of interest will be model acceptability, blood sugar control, end organ damage, and patient engagement in care. A narrative analysis will be conducted, and comparisons made between community-based and facility-based models, where within-study comparison is reported. Conclusion: Care for T2DM has become a global health priority. Community-based care may be an important add-on approach especially in populations with poor access to health care facilities. This review will inform policy makers and program implementers on different community-based models for care of T2DM in SSA, and critically appraise their acceptability and clinical outcomes. It will further identify evidence gaps and future research priorities in community-based T2DM care.",
"keywords": [
"community-based care",
"diabetes mellitus",
"treatment outcome",
"engagement in chronic care",
"access to healthcare",
"sub-Saharan Africa"
],
"content": "Introduction\n\nGlobally, there are about 463 million people living with diabetes mellitus, representing 9.3% of the global population aged 20 – 79 years.1 This number is projected to rise to 700 million people in 2045.1 Approximately 95% of diabetes mellitus cases are due to type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia resulting from a decrease in insulin secretion, or insulin resistance.2,3 The chronic hyperglycemia results in a wide range of long-term complications such as atherosclerosis, coronary heart disease, peripheral neuropathy, diabetic foot syndrome, renal disease and retinopathy.2 The burden of diabetes mellitus disproportionately affects low- and middle-income countries. Of the 700 million projected cases by 2045, low- and middle-income countries will account for an estimated 630 million.4 In sub-Saharan Africa (SSA), 20 million people currently live with diabetes with a projected increase to 47 million people by 2045.5\n\nIt has been reported that in SSA only 50% of persons with T2DM are aware of their diagnosis5 and only 29% of those are engaged in diabetes care.6 Late diagnosis and poor treatment contribute to high rates of T2DM complications in the region,7 with rising cases of retinopathy, nephropathy, and cardiomyopathy.7 As mortality and morbidity due to T2DM are expected to grow substantially in the region, a widely variegated approach to diagnosis and care is essential to increase awareness and treatment coverage. Such approaches should take into account the economic, geographical and socio-cultural characteristics, and the needs of the population.8\n\nCommunity-based healthcare utilizes the various supportive structures in the community such as family, peers, lay health workers, outreach health posts, community-based- and faith-based organizations, to deliver convenient, affordable, and effective care. As part of an integrated health system, community-based care emphasizes the localization of care close to the patient’s residence rather than in a hospital or clinic.9 The advantages of this approach include community ownership of health responsibility, identification and treatment of diseases at an early stage which reduces health costs faced by the patient and the health system.9 Task-shifting from physicians to nurses or lay cadres is an essential component of community-based care.10 In the HIV/AIDS response, task-shifting and community care have yielded positive results, improving linkage to care, engagement in care, and patient clinical outcomes.11–14 T2DM programs could leverage on the lessons learnt and the success of this approach to improve screening and early diagnosis, as well as engagement in care. Currently, however, there is little evidence about T2DM community-based care models in SSA and how they perform with regards to acceptance, clinical endpoints, and long-term patient engagement in care.\n\n\nStudy rationale\n\nTo inform future policies and programs for T2DM in SSA, this scoping review aims to summarize and categorize models of T2DM community-based care among non-pregnant adults in SSA, and to synthesize evidence on acceptance, clinical outcomes, and patient engagement in care. It will further identify evidence gaps and future research priorities in community-based T2DM care.\n\n\nMethod and analysis\n\nWe decided to use the scoping review approach to identify community-based models of T2DM care in SSA as the approach is well-suited to produce an overview of research evidence within the subject area, and on this particular topic. Using this approach, we will not conduct quality appraisal of selected studies, as we anticipate heterogeneity in the studies in terms of design and methodology. However, the scoping review approach will enable us to compile, categorize, and describe the existing evidence and its capacity to contribute to acceptable and quality T2DM care, which will inform practice, policy-making and future research.\n\nWe will conduct this scoping review using the six-stage approach initially developed by Arskey and O’Malley, which has been further refined by Levac et al. (2010) and the Joanna Briggs Institute methods of evidence synthesis, to ensure efficiency, quality, and reproducibility, as well as allow for critical appraisal of the findings.15–17 This approach recommends the following stages:\n\n1. identifying the research question;\n\n2. identifying relevant studies;\n\n3. selecting studies;\n\n4. charting the data;\n\n5. collating, summarising and reporting the results;\n\n6. expert consultation (optional and included).\n\nAn iterative process guided by the PICO framework (Table 1) was undertaken to identify the research questions, following consultations with experts as well as within our longstanding research teams in Switzerland and Lesotho. During this process we realized that we would need to include studies that assess community-based T2DM care models on their own as well as studies that compare community-based T2DM care models versus facility-based models. Thus, question 3 below will only be answered by studies including a comparison. Following this process, three research questions were identified:\n\n1. What kind of community-based T2DM care models among non-pregnant adults exist in SSA?\n\n2. What are clinical outcomes of community-based T2DM care models in SSA in terms of acceptability to both patient and care provider, blood sugar control, end organ damage, and patient engagement in care?\n\n3. How do community-based T2DM care models in SSA perform compared to facility-based care models (within study comparison)?\n\nWe will conduct searches in Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus. The initial search will be developed for Embase (Elsevier). The search string is divided into three parts, namely “community-based care”, “type 2 diabetes” and “sub-Saharan Africa”. The search strategy will include identification of Emtree terms and keywords relating to each part of the search string. The research team will develop the search string iteratively, based on preliminary searches.\n\nIn an initial step, search will be conducted for the concept ‘community-based care’, to identify different terms and keywords used in the literature to describe such out-of-facility care. The first 500 abstracts will be screened by the reviewers (EF, LG, JB, JH, FR) to also identify relevant synonyms. Terms and keywords will be considered ‘care-based community terms and keywords’ if they describe a care, treatment, or management-centred activity outside of a traditional facility setting. Terms and keywords will be considered ‘non-care-based community terms and keywords’ if they only describe activity outside of traditional facility setting without a care, treatment, or management-centred component. In a following step, search will be conducted for the concept ‘care, treatment, or management’. Similarly, the abstracts will be screened for relevant terms and keywords, which will then be combined with the non-care-based community terms and keywords using Boolean and proximity operators; the latter combination will be associated with the care-based community terms and keywords for a final search string for the concept ‘community-based care’; See Figure 1.\n\nCBP = combined with Boolean and proximity operators. ScR = scoping review.\n\nDuring the preliminary search phase, the research team observed that some authors combined the reporting of diabetes mellitus, arterial hypertension or other cardiovascular conditions. Thus, the search string for the disease concept ‘type 2 diabetes mellitus’ will also include terms for hypertension and cardiovascular diseases. The string related to the geographical concept will be developed based on Campbell et al.19 and the United Nations standard country or area codes for statistical use.20\n\nFollowing development of search strings for each concept, the search will be carried out in a stepwise, building block fashion which will be connected to obtain a final total of relevant publications in the database. The search string will then be translated into other databases using Polyglot Search Translator (Systematic Review Accelerator).18 The design of the search strategy will be conducted in consultation with a medical librarian. Details of the search including a preliminary search string are available as extended data on Figshare.21 Language restrictions will not be placed on retrieved studies. Date restrictions will also not be placed on reviewed articles. From articles extracted for full text screening, a forward and backward search will be conducted for relevant references in the selected articles as well as for articles that cite the selected studies.\n\nStudies\n\nWe will include primary studies that have examined community-based models of care among patients with T2DM. Systematic or other reviews on community-based models of care will be included as a source of relevant original publications.\n\nParticipants\n\nWe will include studies that involved adults who have been diagnosed with T2DM using the standard diagnostic criteria. These adults will be resident and receiving care for their condition in sub-Saharan Africa.\n\nIntervention\n\nIntervention will be delivery of care different from the traditional facility-based care model, which attempts to make care available in the community, at patients’ homes or a central, non-formal health facility location where patients with similar conditions can access care. See Table 2 for components of a community-based model of care.\n\n\n\n• Any professional and non-professional cadre\n\n• Doctors, medical non-physician clinicians,nurses, pharmacists, community health workers (and similar), peers, self-care, psychologists and social workers, family members\n\n• Traditional healers (community members not providing western health care approaches\n\n• If non-professional providers: whether the project provides (or not) supervision and training from medical providers (inclusion criteria).\n\n\n\n• Individuals who screen positive for type 2 diabetes mellitus.\n\n\n\n• Outside of the compound of a permanent health care facility. This may include, but not restricted to: community-based settings: outreach services, home-based care, places used for gathering (religious centres, schools, markets, shops) or delivering other services to citizens. Also, it includes e-health interventions.\n\n\n\n• Model foresees a reduction in number of patients visits to the permanent health facility, as compared to the standard of care.\n\n• The community part should not be an add-on to the care at the facility, but substitute some of the patient’s contact with facilities.\n\n\n\n• Long-term medication prescription/distribution\n\n• Point of care monitoring (e.g. with glucometer)\n\n• Long-term lifestyle change support (at least 1 follow up encounter with a care provider)\n\n\n\n• Diagnosis of chronic complications\n\n• Pharmaceutic treatment\n\n• Screening and early diagnosis of disease\n\n• Rehabilitation\n\n• Behavioural interventions, health promotion, education\n\nComparator\n\nWith facility-based care, where available.\n\nOutcome\n\nOf primary interest will be clinical outcomes like blood glucose indices and T2DM complications. Also of interest will be engagement in care, and acceptability of care to patients and providers.\n\nSee Table 3 for details.\n\n\n\n• Individuals aged 18 years and above, all genders, ethnic groups, education levels, socio-economic levels\n\n• Diagnosed with type 2 diabetes mellitus (T2DM) using the standard diagnostic criteria\n\n• In any of Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Congo, Cote d'Ivoire, Equatorial New Guinea, Eritrea, Ethiopia, eSwatini, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, Somalia, South Africa, Sudan (North, South), United Republic of Tanzania, Togo, Uganda, Zaire, Zambia, Zimbabwe.\n\n\n\n• Clinical outcomes: of interest are tasting blood glucose, random blood glucose, glycated haemoglobin (HbA1c), episodes of hypoglycaemia and hyperglycaemia, adherence to T2DM medication, development of complications like retinopathy, nephropathy, diabetic foot syndrome, cardiovascular diseases and cerebrovascular diseases\n\n• Engagement in care\n\n• Acceptability to patients or providers\n\n\n\n• Prospective or retrospective cohorts\n\n• Randomised control trials\n\n• Non-randomised control trials\n\n• Quasi-randomised control trials\n\n• Systematic or other reviews (to screen for additional original articles)\n\n\n\n• Population/target groups\n\n• Type of patients\n\n• Community site\n\n• Health provider cadre\n\n• Frequency of service\n\n• Other services provided within the same care-model, e.g. arterial hypertension, HIV, tuberculosis\n\n\n\n• Incomplete information that impedes full model characterization and definition\n\nInitially, two reviewers (EF and LG) will independently screen abstracts based on the pre-defined inclusion and exclusion criteria. Studies will be classified as ‘included’ if they meet the inclusion criteria, ‘excluded’ as per the inclusion and exclusion criteria, or ‘pending’ if inclusion or exclusion cannot be immediately determined. Afterwards, full texts of all included and pending studies will be retrieved and the two independent reviewers will screen the full text for inclusion. Any disagreements during the screening process will be resolved by a meeting of the reviewers. Studies which were initially included but excluded during screening of the full text will be specifically labelled as such in a table of excluded studies including the reason for exclusion. Studies that were initially ‘pending’ but later included on closer application of criteria to full text will be documented similarly.19\n\nA data extraction tool will be created to electronically capture relevant information from each included study. Extracted data will include information on journal, authors and dates, study design, participants, type of community-based care model, and assessed outcomes (Table 4). The data extraction tool will be piloted on a subset of studies. Where applicable, outcomes in a comparator arm (facility-based care) will be extracted. Similar to the selection process, the extraction of data will be done in duplicate by two researchers independently, and any discrepancies will be iteratively discussed and resolved within the team.\n\nA Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) flow diagram will be used to illustrate final numbers from included/excluded articles to fully reviewed studies. Studies will be grouped according to the type of care model and categorized according to outcomes reported. Study findings will be synthesized using narrative reporting based on themes that emerge from the extracted data. Where outcomes are stated for facility-based care, exploratory within-study comparison of outcomes will be described.\n\nWe will consult experts on community-based diabetes care for input. This input will help to confirm and interpret out findings, as well as contextualize implications of the findings.\n\n\nEthics\n\nEthical clearance will not be required for this study as this review will utilize publicly available data.\n\n\nData availability\n\nNo underlying data are associated with this article.\n\nFigshare: Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: a scoping review search strategy, https://doi.org/10.6084/m9.figshare.14610090.v3.21\n\nThis project contains details of the search string in Embase.\n\nFigshare: PRISMA-P checklist for “Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: a scoping review protocol”, https://doi.org/10.6084/m9.figshare.14762403.v1.22\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 declared.",
"appendix": "Acknowledgements\n\nWe thank Christian Appenzeller from the University of Basel Library for the support in developing as well as peer-reviewing the search strategy.\n\n\nGrant information\n\nThis review is funded by the TRANSFORM grant of the Swiss Agency for Development and Cooperation (SDC) under the ComBaCaL project (Project no. 7F-10345.01.01), obtained by AA and NDL. EF receives his salary from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 801076), through the SSPH+ Global PhD Fellowship Programme in Public Health Sciences (GlobalP3HS).\n\n\nReferences\n\nSaeedi P, Petersohn I, Salpea P, et al.: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019; 157: 107843. PubMed Abstract | Publisher Full Text\n\nAmerican Diabetes A: Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; 37(Suppl 1): S81–S90. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKerner W, Brückel J: Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes. 2014; 122(7): 384–386. PubMed Abstract | Publisher Full Text\n\nDunachie S, Chamnan P: The double burden of diabetes and global infection in low and middle-income countries. Trans R Soc Trop Med Hyg. 2019; 113(2): 56–64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCho NH, Shaw JE, Karuranga S, et al.: IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138: 271–281. PubMed Abstract | Publisher Full Text\n\nMadela S, James S, Sewpaul R, et al.: Early detection, care and control of hypertension and diabetes in South Africa: A community-based approach. Afr J Prim Health Care Fam Med. 2020; 12(1): e1–e9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMbanya JC, Sobngwi E: Diabetes in Africa. Diabetes microvascular and macrovascular disease in Africa. J Cardiovasc Risk. 2003; 10(2): 97–102. PubMed Abstract | Publisher Full Text\n\nMbanya JC, Motala AA, Sobngwi E, et al.: Diabetes in sub-Saharan Africa. Lancet. 2010; 375(9733): 2254–2266. PubMed Abstract | Publisher Full Text\n\nLankester T, Grills NJ: Setting up Community Health and Development Programmes in Low and Middle Income Settings. Oxford University Press; 2019.\n\nHosler JJF, Abrams JA, Godsay S: Combining task shifting and community-based care to improve maternal health: Practical approaches and patient perceptions. Soc Sci Med. 2018; 216: 26–32. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCallaghan M, Ford N, Schneider H: A systematic review of task- shifting for HIV treatment and care in Africa. Hum Resour Health. 2010; 8: 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKoduah Owusu K, Adu-Gyamfi R, Ahmed Z: Strategies To Improve Linkage To HIV Care In Urban Areas Of Sub-Saharan Africa: A Systematic Review. HIV AIDS (Auckl). 2019; 11: 321–332. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMdege ND, Chindove S, Ali S: The effectiveness and cost implications of task-shifting in the delivery of antiretroviral therapy to HIV-infected patients: a systematic review. Health Policy Plan. 2013; 28(3): 223–236. PubMed Abstract | Publisher Full Text\n\nMurray KR, Dulli LS, Ridgeway K, et al.: Improving retention in HIV care among adolescents and adults in low- and middle-income countries: A systematic review of the literature. PLoS One. 2017; 12(9): e0184879. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArksey H, O’Malley L: Scoping studies: towards a methodological framework. Int J Social Res Methodol. 2005; 8(1): 19–32. Publisher Full Text\n\nPeters MDJ, Marnie C, Tricco AC, et al.: Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth. 2020; 18(10): 2119–2126. PubMed Abstract | Publisher Full Text\n\nLevac D, Colquhoun H, O’Brien KK: Scoping studies: advancing the methodology. Implement Sci. 2010; 5: 69. PubMed Abstract | Publisher Full Text | Free Full Text\n\nClark JM, 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\nSouthern Africa_Ovid MEDLINE 03_07_2017: Google Docs. Accessed May 10, 2021. Reference Source\n\nUNSD—Methodology: Accessed May 10, 2021. Reference Source\n\nFirima E, Gonzalez L, Huber J, et al.: Community-based models of care for management of type 2 diabetes mellitus among non-pregnant adults in sub-Saharan Africa: a scoping review search strategy. figshare. J Contribution. 2021. Publisher Full Text\n\nFirima E: Filled PRISMA-P. figshare. J Contribution. 2021. Publisher Full Text"
}
|
[
{
"id": "90061",
"date": "13 Aug 2021",
"name": "Mahmoud M. Werfalli",
"expertise": [
"Reviewer Expertise Evidence-based medicine",
"evidence-based health practices",
"epidemiology",
"prevention and management of diabetes and cardiovascular 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\nTitle\nAre the authors focusing only on sub-Sahara Africa (SSA) or all African countries? Which classification have they used, WHO, IDF, etc.\nIntroduction\n\nPlease elaborate further and explain why the review questions/objectives lend themselves to a scoping review approach. The authors may consider rephrasing the Introduction section to help the readers understand the contributions of this study in an explicit manner. For example, some parts of the content, such as related work, could be moved to a new related work section in particular up-to-date published related work.\nIn SSA there is a wide range of community-based care for diabetes care including for non-pregnant women - for example, in South Africa and other southern countries where most of those models are operating in the community health centers (CHCs) (facility-based) via CHWs in the community. I am wondering in the search strategy, how many articles addressing the community-based models in those facilities would be missed from these communities?\nMethods\n\nStudy design\nI would suggest the review be restricted to RCTs (and possibly other controlled designs but not observational studies), which would make it more likely that a meta-analysis would be appropriate and the review might benefit from the pooling of the data.\nThe authors stated: \"We will conduct this scoping review using the six-stage approach initially developed by Askey and O’Malley, which has been further refined by Levac et al. (2010) and the Joanna Briggs Institute methods of evidence synthesis...\". I would suggest to the authors using the updated framework: Munn et al. 20181:\nAs a precursor to a systematic view. To identify the types of available evidence in a given field. To identify and analyze knowledge gaps. To clarify key concepts/ definitions in the literature. To examine how research is conducted on a certain topic or field. To identify key characteristics or factors related to a concept.\nIdentifying relevant studies\nI would suggest using the African search filter for a comprehensive and strengthing search strategy.\nParticipants\n\"...adults who have been diagnosed with T2DM using the standard diagnostic criteria.\": Please clarify what do you mean by standard? Do the authors mean WHO diagnostic methods or using others?\nIntervention\n\"Intervention will be the delivery of care different from the traditional facility-based care model, which attempts to make care available in the community, at patients’ homes, or a central, non-formal health facility location where patients with similar conditions can access care.\": This is a confusing statement. Please justify as I have mentioned the terms community and facility-based care are used interchangeably.\nComparator\n\"With facility-based care, where available.\": If not available, would it be compared to the usual care in the facility provided that facility doesn't refer to the community center, for example in South Africa?\nOutcome\n\"Of primary interest will be clinical outcomes like blood glucose indices and T2DM complications. Also of interest will be engaged in care, and acceptability of care to patients and providers.\": Please categorize your outcomes as primary outcomes (clinical) and secondary. Please indicate how the authors define acceptability of care and how will be measured?\n\nThanks.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "7613",
"date": "18 Jan 2022",
"name": "Emmanuel Firima",
"role": "Author Response",
"response": "Title Are the authors focusing only on sub-Sahara Africa (SSA) or all African countries? Which classification have they used, WHO, IDF, etc. Author response: We focused only on sub-Saharan Africa, using geographic regions classification according to the methodology of the United Nations Statistics Division. See lines 118 and 119 of the revised manuscript. Introduction Please elaborate further and explain why the review questions/objectives lend themselves to a scoping review approach. The authors may consider rephrasing the Introduction section to help the readers understand the contributions of this study in an explicit manner. For example, some parts of the content, such as related work, could be moved to a new related work section in particular up-to-date published related work. Author response: We have significantly revised the introduction section as well as the study design paragraph of the methods section to further clarify the contributions of this work and why we opted for the scoping review approach. In SSA there is a wide range of community-based care for diabetes care including for non-pregnant women - for example, in South Africa and other southern countries where most of those models are operating in the community health centers (CHCs) (facility-based) via CHWs in the community. I am wondering in the search strategy, how many articles addressing the community based models in those facilities would be missed from these communities? Author response: We understand that some community models of interest emerge or operate in health centers. Working together with a librarian, we attempted to make the search strategy very comprehensive, not excluding such community models. However, since we are interested in community models that are not simply ‘add-ons’ to facility care, in the full-text review, only such models are included. Methods Study design I would suggest the review be restricted to RCTs (and possibly other controlled designs but not observational studies), which would make it more likely that a meta-analysis would be appropriate and the review might benefit from the pooling of the data. Author response: Thank you for this comment. We anticipate very little evidence within this area. Thus, our initial interest is to map out what evidence is available to inform more research. Thus, by restricting to RCTs, we might miss out on models of community care that were possibly being implemented in observational studies. The authors stated: \"We will conduct this scoping review using the six-stage approach initially developed by Askey and O’Malley, which has been further refined by Levac et al. (2010) and the Joanna Briggs Institute methods of evidence synthesis...\". I would suggest to the authors using the updated framework: Munn et al. 2018: ○ As a precursor to a systematic view. ○ To identify the types of available evidence in a given field. ○ To identify and analyze knowledge gaps. ○ To clarify key concepts/ definitions in the literature. ○ To examine how research is conducted on a certain topic or field. ○ To identify key characteristics or factors related to a concept. Author response: This is a good suggestion. We have incorporated statements from this framework. See lines 55 and 56 of the revised manuscript. But we also kept the six-stage approach as clear steps on how we intend to implement the review. Identifying relevant studies I would suggest using the African search filter for a comprehensive and strengthening search strategy. Author response: This has been considered by our librarians in the search. Thank you for the suggestion Participants \"...adults who have been diagnosed with T2DM using the standard diagnostic criteria.\": Please clarify what do you mean by standard? Do the authors mean WHO diagnostic methods or using others? Author response: We mean the WHO diagnostic criteria. We have clarified this on lines 131 and 132 of the revised manuscript, and also added a reference. Thank you for this comment. Intervention \"Intervention will be the delivery of care different from the traditional facility-based care model, which attempts to make care available in the community, at patients’ homes, or a central, nonformal health facility location where patients with similar conditions can access care.\": This is a confusing statement. Please justify as I have mentioned the terms community and facility-based care are used interchangeably. Author response: This statement has been revised to reflect our purpose. See lines 140 and 141. Also, the terms ‘community-based care’ and ‘facility-based care’ have been clarified. See lines 23 to 27. Comparator \"With facility-based care, where available.\": If not available, would it be compared to the usual care in the facility provided that facility doesn't refer to the community center, for example in South Africa? Author response: If the primary study does not compare a community model to facility model, then we will consider that suitable comparison was not available. Outcome \"Of primary interest will be clinical outcomes like blood glucose indices and T2DM complications. Also of interest will be engaged in care, and acceptability of care to patients and providers.\": Please categorize your outcomes as primary outcomes (clinical) and secondary. Please indicate how the authors define acceptability of care and how will be measured? Author response: The outcomes have been clearly categorized into primary and secondary. We intend to define and measure acceptability using scales adopted for each study by the authors. See lines 147 to 150 of the revised manuscript. Thank you."
}
]
},
{
"id": "97772",
"date": "15 Nov 2021",
"name": "Anna Wahyuni Widayanti",
"expertise": [
"Reviewer Expertise Medicine taking behavior of and community-based intervention for people with type 2 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\nIn the introduction, could you please explain further how the people with diabetes in SSA countries received care in general? This may include the differences in the health system, that may lead to variabilities in the care types.\nPlease be clearer in stating the rationale of the study. At the beginning, the authors only explained about community-based care, but later the authors also want to investigate the performance of community-based care compared to facility-based care.\nIt should be clearer what 'facility-based care' and 'community-based care' mean? As in other country settings, the community-based care for people with diabetes may include care managed by the health care facility, it may be conducted in the health care facilities or in the community, but in groups of community and involving not only health care professionals, but also community volunteers/cadres, as opposed to individual care provided by health care professionals.\nA systematic review may provide a better results in comparing effectiveness among different types of community-based care.\nIdentifying relevant study: Is there any time frame set for the articles that will be included in the review?\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "7614",
"date": "18 Jan 2022",
"name": "Emmanuel Firima",
"role": "Author Response",
"response": "In the introduction, could you please explain further how the people with diabetes in SSA countries received care in general? This may include the differences in the health system, that may lead to variabilities in the care types. Author response: We have addressed this and included a traditional approach to care in the revised version of the manuscript on lines 20 to 25 of the revised manuscript. Please be clearer in stating the rationale of the study. At the beginning, the authors only explained about community-based care, but later the authors also want to investigate the performance of community-based care compared to facility-based care. Author response: Even though our main interest is to present evidence on available community-based care models, we intend to evaluate performance against community-based care in studies where comparisons are made between community-based care and facility-based care. This has been clarified in the rationale. See lines 50 to 52. It should be clearer what 'facility-based care' and 'community-based care' mean? As in other country settings, the community-based care for people with diabetes may include care managed by the health care facility, it may be conducted in the health care facilities or in the community, but in groups of community and involving not only health care professionals, but also community volunteers/cadres, as opposed to individual care provided by health care professionals. Author response: Thank you for these comments. We have clarified the term ‘community-based care’ and ‘facility-based care’ in lines 26 to 30. A systematic review may provide a better results in comparing effectiveness among different types of community-based care. Author response: As this is an area with little evidence, we opted to conduct a scoping review to map out what evidence is available. Identifying relevant study: Is there any time frame set for the articles that will be included in the review? Author response: There is no restriction on the time/date the study was conducted. See lines 126 and 127 of the revised manuscript. Thank you."
}
]
}
] | 1
|
https://f1000research.com/articles/10-535
|
https://f1000research.com/articles/11-58/v1
|
18 Jan 22
|
{
"type": "Software Tool Article",
"title": "ProSGPV: an R package for variable selection with second-generation p-values",
"authors": [
"Yi Zuo",
"Thomas G. Stewart",
"Jeffrey D. Blume",
"Thomas G. Stewart",
"Jeffrey D. Blume"
],
"abstract": "We introduce the ProSGPV R package, which implements a variable selection algorithm based on second-generation p-values (SGPV) instead of traditional p-values. Most variable selection algorithms shrink point estimates to arrive at a sparse solution. In contrast, the ProSGPV algorithm accounts for the estimation uncertainty – via confidence intervals – in the selection process. This additional information leads to better inference and prediction performance in finite sample sizes. ProSGPV maintains good performance even in the high dimensional case where $p>n$, or when explanatory variables are highly correlated. Moreover, ProSGPV is a unifying algorithm that works with continuous, binary, count, and time-to-event outcomes. No cross-validation or iterative processes are needed and thus ProSGPV is very fast to compute. Visualization tools are available in this package for assessing the variable selection process. Here we present simulation studies and a real-world example to demonstrate ProSGPV’s inference and prediction performance in relation to the current standards in variable selection procedures.",
"keywords": [
"R",
"variable selection",
"statistical inference"
],
"content": "Introduction\n\nAs the sheer volume of data grows at an astronomical rate, variable selection plays an increasingly crucial role in research. This is particularly true in the high dimensional setting where p>n and classical statistical methods exploiting the full feature space no longer work. An ideal variable selection procedure would recover the underlying true support with high probability, yield parameter estimation with low bias, and achieve good prediction performance. While it is hard for a statistical procedure to strike a balance between inference and prediction tasks,1,2 the ProSGPV algorithm is remarkably able in this sense.3,4\n\nOne natural approach to variable selection is best subset selection (BSS). BSS chooses k out of p total variables for each k∈12…p that maximize a chosen loss function. It can be thought of as an ℓ0-penalized regression.5 showed that the BSS problem is nonconvex and NP-hard. With recent advancements,6–8 solving the BSS routine with thousands of features is no longer infeasible. Particularly, an efficient R package called BeSS8 is scalable to identify the best sub-model in seconds or a few minutes when p is around 10,000. ℓ1-penalized likelihood procedures are also used for variable selection. Lasso, for example, produces models with a strong predictive ability.9 However, lasso is not always variable selection consistent.1,10 To address the inconsistency issue, adaptive lasso was proposed, which introduces weights in the ℓ1 penalty.11 Despite oracle variable selection properties of the adaptive lasso, it is often hard in practice to find a tuple of tuning parameters that achieve the properties. Both lasso and adaptive lasso can be implemented in the glmnet package.12,13 Smoothly clipped absolute deviation (SCAD)14 and minimax concave penalty with penalized linear unbiased selection (MC+)15 were proposed to bridge the gap between the ℓ0 and ℓ1 penalties. The two algorithms are largely distinguished by their piecewise linear thresholding functions. Sure independence screening (SIS),16,17 implemented in the SIS package,18 ranks the maximum marginal likelihood estimates and can greatly reduce the dimensionality of feature space by keeping top variables in the ranking, even when p≫n. Iterative SIS (ISIS) can improve its performance in finite sample sizes. Note that all aforementioned algorithms shrink point estimates to derive a sparse solution and there is room for improvement of inference and prediction properties in finite sample sizes.\n\nMany R packages have been developed to address certain data types. For example, clogitL119 performs variable selection with lasso and elastic net penalties in conditional logistic regression; pogit20 performs Bayesian variable selection with spike and slab priors in Poisson and Logistic regressions; penPHcure21 performs variable selection in Cox proportional hazards cure model with time-varying covariates. The ideal R package would have superior or comparable performance as the current algorithms, and work with each of continuous, binary, count, and time-to-event outcomes.\n\nRecently, we3,4 developed penalized regression with second generation p-values (ProSGPV) for variable selection in both low-dimensional (n>p) and high-dimensional (p>n) settings. Unlike traditional algorithms, ProSGPV incorporates estimation uncertainty via confidence intervals in the variable selection process. This addition often leads to better support recovery, parameter estimation, and prediction performance. This paper describes an R package named ProSGPV, which implements the ProSGPV algorithm.29 Here, we extend the algorithm to work with data from logistic regression, Poisson regression, and Cox proportional hazards regression. We also provide visualization tools for variable selection process, which was not discussed in the original paper.3,4 Simulation studies below compare the inference and prediction performance of ProSGPV against that of glmnet, BeSS, and ISIS, in scenarios not discussed in.3,4 A real-world example compares the sparsity of solutions and prediction accuracy of all algorithms.\n\n\nMethods\n\nSecond-generation p-values (SGPVs) were proposed to address some of the well-known flaws in traditional p-values.22,23 The basic idea is to replace the point null hypothesis with a pre-specified interval null. The SGPV is denoted by pδ, where δ represents the half-width of the interval null. The interval null represents the set of effect sizes that are scientifically indistinguishable from the point null hypothesis, due to limited precision or practicality.\n\nSGPVs are essentially the fraction of data-supported hypotheses that are also null hypotheses. See Figure 1 for an illustration of how SGPVs work. Their formal definition is as follows: let θ be the parameter of interest, and let I=θlθu be an interval estimate of θ whose length is given by |I|=θu−θl. Here, I can be a confidence interval (we will use 95% CIs in this paper) or likelihood support interval or a credible interval. The coverage probability of the interval estimate I will largely drive the frequency properties of the SGPV upon which it is based.\n\nDenote the length of the interval null by |H0|. Then the SGPV, pδ, is defined as\n\nNotice also that the correction term maxI/2H01 resolves any problems that arise when the interval estimate I is too wide to be useful or reliable, in which case the data are effectively deemed inconclusive. It is in this way that SGPVs emphasize effects that are clinically meaningful over effects that are small and near the null hypothesis. Empirical studies have shown how SGPVs can be used to identify feature importance in high dimensional settings.3,4,22,23 The null bound in the SGPVs is typically the smallest effect that would be clinically relevant or the effect magnitude that can be distinguished from noise, on average.3,4 proposed using a generic null interval for regression coefficients that shrinks to zero and is based on the observed level of noise in the data. This extends the null bound in22,23 that remains constant. The interval is easily obtained in the variable selection step and promotes good statistical properties in the selection algorithm.\n\nThe ProSGPV algorithm is a two-stage algorithm. In the first stage, the algorithm identifies a candidate set of variables using a broad regularization scheme. In the second stage, the algorithm applies SGPV regularization to the model based on the candidate set identified in the first stage. The successive regularization approach is easy and fast to implement, and quite accurate for screening out false features. The steps of the ProSGPV algorithm are shown in Algorithm 1.\n\nAlgorithm 1. The ProSGPV algorithm.\n\n1: procedure ProSGPV(X, Y)\n\n2: Stage one: Find a candidate set\n\n3: Fit a lasso and evaluate it at λgic\n\n4: Fit OLS/GLM/Cox models on the lasso active set\n\n5: Stage two: SGPV screening\n\n6: Extract the confidence intervals of all variables from the previous step\n\n7: Calculate the mean coefficient standard error SE¯\n\n8: Calculate the SGPV for each variable where Ij=β̂j±1.96×SEj and H0=−SE¯SE¯\n\n9: Keep variables with SGPV of zero\n\n10: Refit the OLS/GLM/Cox with selected variables\n\n11: end procedure\n\nBy default, data are scaled and centered in linear regression but are not transformed as such in GLM and Cox regression. No notable difference is observed when data are standardized in GLM and Cox regression. In the first stage, lasso is used to reduce the feature space to a candidate set that is very likely to contain true signals. This pre-screening is crucial to high dimensional data (n<p) and improves the support recovery and parameter estimation in low dimensional data.3 The lasso is evaluated at λgic, but the algorithm is robust with respect to the choice of λ.3 In the second stage, the null bound is set to be the mean standard error of all coefficient estimates. However, the algorithm is insensitive to any reasonable scale change in the null bound.3,4 When data are highly correlated, a generalized variance inflation factor (GVIF)24 adjusted null bound can be used to improve the inference and prediction performance.4\n\nIn essence, ProSGPV is a hard thresholding algorithm that shrinks small effect to zero and reserve the large effect to obtain an unbiased estimate when the true support is successfully recovered. Notation-wise, the solution to the ProSGPV algorithm β̂prosgpv is\n\nWhen λgic in Algorithm 1 is replaced with zero in the first stage, ProSGPV reduces to a one-stage algorithm. That amounts to calculating SGPVs for each variable in the full model and select variables whose effects are above the threshold. However, the support recovery and parameter estimation performance of the one-stage algorithm is slightly worse than that of the two-stage algorithm.3 Moreover, the one-stage algorithm is not applicable when p>n, i.e. when the full OLS/GLM/Cox model is not identifiable.\n\nThe ProSGPV package is publicly available from the Comprehensive R Archive Network (CRAN), a development version is available on GitHub, and is archived with Zenodo.29 To install from CRAN, please run\n\nTo install a development version, please run\n\nThe main function pro.sgpv implements the default two-stage and optional one-stage ProSGPV algorithm. User-friendly print, coef, summary, predict, and plot functions are equipped with pro.sgpv for both one- and two-stage algorithms. Jeffreys prior penalized logistic regression25 is used when the outcome is binary to stabilize coefficient estimates in the case of complete/quasi-complete separation. In the next section, we demonstrate how pro.sgpv works with simulated continuous outcome data.\n\nThe ProSGPV package works across different platforms (Windows, mac OS, and Linux). The R version number should be greater than 3.5.0. Once installed, the workflow is described as below. We first present an example by applying the ProSGPV algorithm to a simulated dataset by use of gen.sim.data function. With sample size n = 100, number of variables p = 20, number of true signals s = 4, smallest effect size βmin = 1, largest effect size βmax = 5, autoregressive correlation ρ = 0.2 and variance σ2 = 1, signal-to-noise ratio (SNR) defined in26 ν = 2, we generate outcomes Y following Gaussian distribution. gen.sim.data outputs X, Y, indices of true signals, and a vector of true coefficients.\n\nBy default, the two-stage algorithm is used in ProSGPV. pro.sgpv function takes inputs of explanatory variables x, outcome y, outcome type family (default is “gaussian”), stage indicator (default is 2), and a GVIF indicator (default is FALSE). A print method is available to show labels of the variables selected by ProSGPV.\n\nThe variable selection process can be visualized by using the plot function. Figure 2 shows the fully relaxed lasso path along a range of λs. The shaded area is the null zone and any effect whose 95% confidence interval overlaps with the null region will be considered irrelevant or insignificant. ProSGPV is evaluated at λgic. The lpv argument can be used to choose to display one line per variable (the confidence bound that is closer to the null region) or three lines per variable (an point estimate and confidence bounds, default). The lambda.max argument control the limit of the x-axis in the plot.\n\nsummary function outputs the regression summary of the selected model. When the outcome is continuous, an OLS is used.\n\n\n\n\n\n\n\n\n\ncoef function can be used to extract the coefficient estimates of length p. When signals are sparse, some of estimates are zero. A comparison shows that the estimates are close to the true effect sizes in the simulation.\n\n\n\npredict function can be used to predict outcomes using the selected model. In-sample prediction can be made by calling predict (sgpv.out.2) and out-of-sample prediction can be made by feeding new data set into the newdata argument.\n\nIn addition to the two-stage algorithm, one-stage algorithm can also be used to select variables when n > p. The computation time is shorter for the one-stage algorithm at the expense of slightly reduced support recovery rate in the limit, as shown in.3 Figure 3 shows the variable selection result of the one-stage algorithm on the same data. The one-stage algorithm missed V4 and only selected three variables. The lower confidence bound of the estimate for V4 barely excludes the null region, and was dropped from the final model because of that. The one-stage algorithm illustrates how estimation uncertainty via confidence intervals (horizontal segments) can be incorporated in variable selection.\n\nExamples of binary, count, and time-to-event data can be found in the package vignettes.\n\nSimulation design is adapted from3,4 and we will present below scenarios not discussed in those two papers. The setup can be found in the Table 1 below. The scale and shape parameters are used to generate time-to-event from a Weibull distribution. ProSGPV is compared against lasso, BeSS, and ISIS. Results are aggregated over 1000 simulations. Evaluation metrics include support recovery rate, parameter estimation mean absolute error (MAE), prediction root mean square error (RMSE) and area under the curve in a separate test set. Support recovery is defined as capturing the exact true support, not containing. An estimate of MAE is 1/p∑j=1p∥β̂j−β0,j∥, where β0,j is the jth true coefficient. Simulation results are summarized in Figure 4.\n\nA) Average support recovery rate, means surrounded by 95% Wald confidence intervals. B) Average mean absolute error, medians surrounded by 1st and 3rd quartiles. C) Prediction accuracy in a separate test set (root mean square error for linear and Poisson regressions, and area under the curve for Logistic regression), medians surrounded by 1st and 3rd quartiles. D) Average running time in seconds, medians surrounded by 1st and 3rd quartiles. Values are censored at 0.8 seconds for aesthetic reasons.\n\nFrom Figure 4, we observe similar results as in.3,4 ProSGPV often has the highest capture rates of the exact true model, has lowest parameter estimation bias, has one of the lowest prediction error, and is the fastest to compute. Note that GVIF-adjusted null bound is used in the Logistic regression because of the high correlation in the design matrix.\n\n\nResults\n\nIn this section, we compare the performance of ProSGPV with lasso, BeSS, and ISIS algorithms using a real-world financial data.28 The close price of Dow Jones Industrial Average (DJIA) was documented from Jan 1, 2010 to November 15, 2017 and eight groups of primitive, technical indicators, big U.S. companies, commodities, exchange rate of currencies, future contracts and worlds stock indices, and other sources of information27 were collected to predict the DJIA close price. In the analyzed data with complete records, there are 1114 observations and 82 predictors. We randomly sampled 614 observations as a fixed test set to evaluate the prediction performance of models built on the training set. We allowed the training set size n to vary from 40 to 300. At each n, we recorded the distribution of the training model size for each algorithm as well as the distribution of the prediction RMSE over 1000 repetitions. Results are summarized in Figure 5. ProSGPV and lasso had sparser models than BeSS and ISIS did, while ProSGPV had much better prediction performance in the test set. BeSS and ISIS had better prediction performance at the cost of including much more variables in the final model. The tradeoff between the sparsity of solutions and prediction accuracy is well illustrated in this example. Variables frequently selected by ProSGPV include 5-, 10-, and 15-day rate of change, and 10-day exponential moving average of (DJIA). Technical indicators seem more predictive than other world indices, commodity, exchange rate, futures, etc.\n\nMedians as well as 1st and 3rd quartiles from 1000 repetitions are compared.\n\n\nConclusions\n\nWe introduced an R package to implement the ProSGPV algorithm, a variable selection algorithm that incorporates estimation uncertainty via confidence intervals. This novel addition often leads to better support recovery, parameter estimation, and prediction performance. The package is user-friendly, has nice visualization tools for the variable selection process, facilitates subsequent inference and prediction, and very fast computationally. The efficacy of our package is demonstrated on both simulation and real-world data sets.\n\n\nData availability\n\nThe real-world data are from a Kaggle data challenge, which is available at https://www.kaggle.com/ehoseinz/cnnpred-stock-market-prediction. Detailed description of data elements can be found in.27\n\nZenodo: zuoyi93/r-code-prosgpv-r: v1.0.0. https://doi.org/10.5281/zenodo.5655772.28\n\n• Processed_DJI.csv (real-world 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\nExtended data\n\nAnalysis code available from: https://github.com/zuoyi93/r-code-prosgpv-r/tree/v1.0.0#readme\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.5655772.28\n\nLicense: Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nSoftware availability\n\nSoftware available from: https://cran.r-project.org/web/packages/ProSGPV/index.html\n\nSource code available from: https://github.com/zuoyi93/ProSGPV\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.5655795.29\n\nLicense: 3-Clause BSD License.",
"appendix": "References\n\nMeinshausen N, Bühlmann P: High-dimensional graphs and variable selection with the lasso. Ann. Stat. 2006; 34(3): 1436–1462. Publisher Full Text\n\nShmueli G: To explain or to predict?. Stat. Sci. 2010; 25(3): 289–310. Publisher Full Text\n\nZuo Y, Stewart TG, Blume JD: Variable selection with second-generation p-values. Am. Stat. 2021; 1–11. Publisher Full Text\n\nZuo Y, Stewart TG, Blume JD: Variable selection in glm and cox models with second-generation p-values. arXiv preprint arXiv:2109.09851. 2021.\n\nNatarajan BK: Sparse approximate solutions to linear systems. SIAM J. Comput. 1995; 24(2): 227–234. Publisher Full Text\n\nHazimeh H, Mazumder R: Fast best subset selection: Coordinate descent and local combinatorial optimization algorithms. Oper. Res. 2020; 68(5): 1517–1537. Publisher Full Text\n\nDi Gangi L, Lapucci M, Schoen F, et al.: An efficient optimization approach for best subset selection in linear regression, with application to model selection and fitting in autoregressive time-series. Comput. Optim. Appl. 2019; 74(3): 919–948. Publisher Full Text\n\nWeng H, Feng Y, Qiao X: Regularization after retention in ultrahigh dimensional linear regression models. Stat. Sin. 2019; 29(1): 387–407. Publisher Full Text\n\nTibshirani R: Regression shrinkage and selection via the lasso. Journal of the Royal Statistical Society: Series B (Methodological). 1996; 58(1): 267–288. Publisher Full Text\n\nLeng C, Lin Y, Wahba G: A note on the lasso and related procedures in model selection. Stat. Sin. 2006; 1273–1284.\n\nZou H: The adaptive lasso and its oracle properties. J. Am. Stat. Assoc. 2006; 101(476): 1418–1429. Publisher Full Text\n\nFriedman J, Hastie T, Tibshirani R: Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 2010; 33(1): 1–22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSimon N, Friedman J, Hastie T, et al.: Regularization paths for cox’s proportional hazards model via coordinate descent. J. Stat. Softw. 2011; 39(5): 1–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFan J, Li R: Variable selection via nonconcave penalized likelihood and its oracle properties. J. Am. Stat. Assoc. 2001; 96(456): 1348–1360. Publisher Full Text\n\nZhang C-H: Nearly unbiased variable selection under minimax concave penalty. Ann. Stat. 2010; 38(2): 894–942. Publisher Full Text\n\nFan J, Lv J: Sure independence screening for ultrahigh dimensional feature space. Journal of the Royal Statistical Society: Series B (Statistical Methodology). 2008; 70(5): 849–911. Publisher Full Text\n\nFan J, Song R: Sure independence screening in generalized linear models with np-dimensionality. Ann. Stat. 2010; 38(6): 3567–3604. Publisher Full Text\n\nSaldana DF, Feng Y: Sis: An r package for sure independence screening in ultrahigh-dimensional statistical models. J. Stat. Softw. 2018; 83(1): 1–25.\n\nReid S, Tibshirani R: Regularization paths for conditional logistic regression: the clogitl1 package. J. Stat. Softw. 2014; 58(12): Publisher Full Text\n\nDvorzak M, Wagner H: Sparse bayesian modelling of underreported count data. Stat. Model. 2016; 16(1): 24–46. Publisher Full Text\n\nBeretta A, Heuchenne C: penphcure: Variable selection in proportional hazards cure model with time-varying covariates. R Journal. 2021; 13(1). Publisher Full Text\n\nBlume JD, D’Agostino McGowan L, Dupont WD, et al.: Second-generation p-values: Improved rigor, reproducibility, & transparency in statistical analyses. PloS One. 2018; 13(3): e0188299. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBlume JD, Greevy RA, Welty VF, et al.: An introduction to second-generation p-values. Am. Stat. 2019; 73(sup1): 157–167. Publisher Full Text\n\nFox J, Monette G: Generalized collinearity diagnostics. J. Am. Stat. Assoc. 1992; 87(417): 178–183. Publisher Full Text\n\nKosmidis I, Firth D: Jeffreys-prior penalty, finiteness and shrinkage in binomial-response generalized linear models. Biometrika. 2021; 108(1): 71–82. Publisher Full Text\n\nHastie T, Tibshirani R, Tibshirani R: Best subset, forward stepwise or lasso? analysis and recommendations based on extensive comparisons. Stat. Sci. 2020; 35(4): 579–592. Publisher Full Text\n\nHoseinzade E, Haratizadeh S: Cnnpred: Cnn-based stock market prediction using a diverse set of variables. Expert Syst. Appl. 2019; 129: 273–285. Publisher Full Text\n\nZuo Y: zuoyi93/r-code-prosgpv-r: v1.0.0 (v1.0.0). Zenodo. 2021. Publisher Full Text\n\nZuo Y: ProSGPV R package v1.0.0. Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "120267",
"date": "26 Jan 2022",
"name": "Georg Heinze",
"expertise": [
"Reviewer Expertise biostatistics",
"clinical epidemiology",
"prognosis 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 paper describes an R-package with which a recently proposed method of variable selection, ProSGPV, can be applied to data sets. I am not fully convinced of the method. It would need a neutral comparison study (one not conducted by the authors who invented the method) to prove if it's useful. But to conduct such a study, an efficient implementation of the method is needed, which is introduced in this report. So the paper has some relevance. Introduction: 'classical statistical methods exploiting the full feature space no longer work': but any variable selection algorithm would have to exploit the full feature space when searching for predictive variables? One may be interested in getting a sparse solution because one assumes that only a small subset of features is really predictive, or if a smaller prediction model has other advantages, e.g. costs or practicability. But there are many modeling techniques that do not sparsify the feature space which works very well with high-dimensional data such as ridge regression. So more convincing arguments for the need for data-driven variable selection should be given. Figure 1 may need some more explanations in the caption. At step 9 of the algorithm, only variables with a SGPV of zero are kept. What if two variables have a high correlation and both of their SGPV are greater than zero, but omitting them both from the model would reduce the information significantly. Isn't this a drawback of this procedure? Why not sequentially (one-by-one) eliminating variables and refitting the model? In the definition of the null interval, the authors speak of 'minimum clinical relevance' (so having medical applications in mind), but the example is from the financial world. Could the authors give some idea how to define the null interval for other areas of application? It seems that the SGPV depends on the confidence levels because with lower confidence levels, the intervals are shorter and the probability to get SGPV of 0 gets larger. The empirical null interval definition seems a bit arbitrary (mean of standardized standard errors). Why not the root of the mean of standardized variances? Why take the mean at all? Does this imply any assumptions on an equal a-priori importance of the variables? What about correlated variables? In the simulation study, the authors confounded the type of regression with varying n or p. This simulation can only be seen as proof that the package works, but I am not so convinced yet that it also proves the advantages of the new method. So the results still have to be interpreted with caution. We don't know if the simulation scenarios were pre-specified or selected after the fact, and if the simulated joint covariates-outcome distributions are representative of any real data sets one encounter in practice.\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? Partly",
"responses": [
{
"c_id": "7786",
"date": "01 Mar 2022",
"name": "Yi Zuo",
"role": "Author Response",
"response": "Dear Dr. Heinze, Thank you for taking the time to review our paper. We appreciate your thoughtful comments and we think these concerns can be readily addressed. Please see our responses below. Comment 1 Introduction: 'classical statistical methods exploiting the full feature space no longer work': but any variable selection algorithm would have to exploit the full feature space when searching for predictive variables? One may be interested in getting a sparse solution because one assumes that only a small subset of features is really predictive, or if a smaller prediction model has other advantages, e.g. costs or practicability. But there are many modeling techniques that do not sparsify the feature space which works very well with high-dimensional data such as ridge regression. So more convincing arguments for the need for data-driven variable selection should be given. Response: The issue is not that the methods exploit the full feature space, but rather how they do it. Our comment was in the context of p>n, i.e. when there are more features than samples. In this setting, many of the classical approaches, like stepwise regression, are unable to fit all of the candidate models due to lack of data. While a ridge regression would be useful for prediction, it does not eliminate any features and is therefore not considered a “variable selection” algorithm. The sparsity assumption is commonly accepted in many applications. Also, small here is relative to the size of the entire feature space (including all interactions and non-linear terms) which is often quite big. So sparseness is not all that constraining in practice. Comment 2a Figure 1 may need some more explanations in the caption. At step 9 of the algorithm, only variables with a SGPV of zero are kept. What if two variables have a high correlation and both of their SGPV are greater than zero, but omitting them both from the model would reduce the information significantly. Isn't this a drawback of this procedure? Why not sequentially (one-by-one) eliminating variables and refitting the model? Response: When data are highly correlated, successful support recovery happens less often (it happens less often for all approaches). Lasso screening handles highly correlated feature sets well, which is why we use it in the first stage. In addition, using the generalized variance inflation factor (GVIF) proposed in improves the performance of the ProSGPV algorithm. Details can be found in . But we do not see this as a drawback of the procedure, as it continues to outperform competitors. Regarding sequential elimination, what you propose is similar to backward/stepwise regression only with SGPVs. When we first explored our algorithm, we did explore this procedure and found that it leads to poor variable selection performance, especially when there are minor changes to the data. Its performance did not warrant us mentioning it in the paper. In addition, sequentially dropping variables adds increases the computation burden when the number of candidate variables is large. By contrast, our proposed method is much more efficient. Comment 2b In the definition of the null interval, the authors speak of 'minimum clinical relevance' (so having medical applications in mind), but the example is from the financial world. Could the authors give some idea how to define the null interval for other areas of application? It seems that the SGPV depends on the confidence levels because with lower confidence levels, the intervals are shorter and the probability to get SGPV of 0 gets larger. This is a good question. We addressed this directly with sensitivity analysis in Supplementary Figure 1 in < DOI: 10.1080/00031305.2021.1946150>. The major difference with this SPGV implementation is that the null zone, because it is the average standard error of the standardized coefficients, shrinks to zero as the sample size grows. Hence our approach is less sensitive to the specification of the zone. However, this is not necessarily surprising, as argued that in order to achieve optimal properties of variable selection, the amount of lasso shrinkage must be proportional to the standard error of the maximum likelihood estimates of coefficients. As for the dependence on the confidence interval coefficient, this is unavoidable. The SGPV framework chooses to make this connection explicit so that it is easy for the user to know what the upper bound on the Type I error rate is (it is one minus the confidence interval coefficient). This clearly affects the frequency properties of the overall procedure in the same way that setting the Type I error cutoff for stepwise regression does. Comment 3 The empirical null interval definition seems a bit arbitrary (mean of standardized standard errors). Why not the root of the mean of standardized variances? Why take the mean at all? Does this imply any assumptions on an equal a-priori importance of the variables? What about correlated variables? Response: As we mentioned above, the choice of the null bound was inspired by . In linear regression, we do standardize all explanatory variables so that the standard errors are comparable, and, in this setting, it makes sense to average them. In GLM/Cox regression, we observed in the simulation studies that standardization does not affect the support recovery, so we abandoned it to reduce computation steps. When data are highly correlated, GVIF is used to adjust the null bound which improves the support recovery performance. Comment 4 In the simulation study, the authors confounded the type of regression with varying n or p. This simulation can only be seen as proof that the package works, but I am not so convinced yet that it also proves the advantages of the new method. So the results still have to be interpreted with caution. We don't know if the simulation scenarios were pre-specified or selected after the fact, and if the simulated joint covariates-outcome distributions are representative of any real data sets one encounter in practice. Response: We find this argument specious. It is certainly possible that some simulation settings yield excellent results while others, close in the parameter space, do not. While this is not the case here – we found no evidence of highly erratic behavior – no amount of simulating can address this concern. We prepared extensive simulations by varying n, p, s (sparsity of the solution), effect size, correlation structure, and signal-to-noise ratio. There is simply no way to report on them all; however, the general patterns of behavior are consistent, and this is what we report. In all cases considered, our proposed algorithm had one of the best support recovery performances, nearly optimal parameter estimation properties, and acceptable prediction performance. Note that when the effect size is small or the signal-to-noise ratio is low, none of the algorithms we considered yielded good results. That said, our code is accessible and easy to use, and we encourage double-checking and reproduction of our results."
}
]
},
{
"id": "159039",
"date": "08 Feb 2024",
"name": "Enrico Ripamonti",
"expertise": [
"Reviewer Expertise Statistics"
],
"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 found the authors' report clear, concise, and effective. I do not have further comments or suggestions. Maybe, as a proposal for the future, a vignette could be created and posted in the CRAN. This could be useful for practitioners willing to use this package and also for students and the applied community.\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": []
}
] | 1
|
https://f1000research.com/articles/11-58
|
https://f1000research.com/articles/10-1034/v1
|
11 Oct 21
|
{
"type": "Research Article",
"title": "Do Maya women have the chance to improve their quality of life?",
"authors": [
"Anna Siniarska",
"Napoleon Wolański",
"Anna Siniarska"
],
"abstract": "Background: Maya families suffered greatly during the henequen industry in the Yucatan, but the lives of the Maya women at the time were perhaps worse than anywhere in the world. Changes in Maya body height over the 20th century were assessed in order to show secular changes. The use of the sexual dimorphism index (SDI) allowed for the evaluation of the living conditions prevailing during the existence of the henequen haciendas to the Mexican revolution and a gradual improvement of these conditions by the end of the 20th century. Methods: In 1994, 364 men and 320 women aged 20-98 years were studied in Merida, Yucatan, Mexico. They were divided into six age groups and by gender: 20-29, 30-39, 40-49, 50-59, 60-69 and 70+ years. Stature for both genders, and age at menarche for women were considered. SDI in stature was calculated to assess living conditions. Results: There were smaller (0.25 cm/10 years) changes in height in men than in women (0.9 cm/10 years) and no significant changes in acceleration of maturation. SDI results showed changes from 9.9 to 7.6, and this may indicate a constant, but very small improvement of living conditions. The age at menarche of women did not show statistically significant acceleration with age. Conclusions: In the colonial period of the late 19th century until the Mexican Revolution, women were worse off than men. Previous research has shown that when living conditions change, men always react faster than women, e.g. by lowering or increasing body height. Our study of the Maya population in the 20th century showed otherwise; female height increased more than male height. This may reflect that the living conditions of Maya men have not changed over the 20th century, but have improved for women.",
"keywords": [
"Mayas",
"sexual dimorphism",
"secular changes",
"violence against women"
],
"content": "Introduction\n\nJames Tanner wrote that the average height of people in any society is a mirror that “reflects rather accurately the material and moral conditions of that society” (Tanner, 1986). Simply stated, height reflects the quality of life. Maya women of southern Mexico and Guatemala have the shortest stature of all non-Pygmy women and that has been so for at least 100 years (NCD-RisC, 2016).\n\nMayan life in the late 19th and at the turn of the 20th centuries was closely related to the cultivation of henequen fiber. At that time the daily lives of Maya families had a great impact on their biological status. The description of the relationship between the hacienda workers and the henequen industry, using supporting literature, is important here. This is for evaluation, in both sexes separately, changes in body height with age, changes in sexual dimorphism index (SDI) with age, which describes living conditions and changes in women’s age of maturation using age at menarche.\n\nWith the arrival of the Spaniards in the 16th century, the cultivation of henequen fiber became a mass industry that flourished in the mid-19th century (Rioux, 2014). There were many haciendas (large agricultural estates or plantations) in Spanish-speaking countries, especially in Mexico, and from the mid-18th century these grew in size and economic power for almost a hundred years. In the Yucatan region of Mexico, the haciendas started as maize and sugar plantations, but later they became henequen estates.\n\nThe haciendas were independent organizations employing hundreds of workers, arranged according to a certain structure. The most important in the hierarchy were the landowners, then the haciendados (people to whom the land was gifted along with peons - unskilled farm workers), at the bottom there were Maya people (Kumar, 2019). Haciendas were typically composed of a variety of different structures, including a main house, a kitchen, a warehouse, servant quarters, worker housing, stables, a church, a store, a cemetery, a pigsty, roping areas, gardens or fields, and even prisons. It maintained huge fields of henequen, tended by hundreds of men. The main house, or Casa Principal, was usually the largest building, where the haciendado kept his living quarters and where most of the administration occurred (Kumar, 2019; Wells, 1985). Plants had machines to produce henequen fibers and ropes which were shipped worldwide from the port of Sisal (Kumar, 2019).\n\nFrom the end of the 19th century to the 1920s, for around 40 years, henequen was the basic industry of Yucatán. This resulted in Yucatán becoming the richest state of Mexico (Brannon & Baklanoff, 1987). By this time, the henequen plant was called “green gold”. But henequen had been present in the life of Mayan society since pre-conquest times. The plant was often grown outside of houses, along roads and outside of towns (Rejón, 2006). A major use for the henequen fiber was rope to fasten and pull, and as material for sandals, hunting bows and traps, roofing thatch, fishing nets, hammocks, bags to transport different items (e.g. corn seed) or other framing tools to cultivate milpas (fields cleared of forest where farmers plant more than a dozen plants at once, including corn, avocado, many varieties of squash and bean, melon, tomatoes and the like). Henequen fiber was also used to drill teeth, and the sharp spines of henequen leaves were used as needles. In addition, prisoners of war were bound with henequen rope, juices from Agava were used to make wine, and henequen also could be a decoration (Rioux, 2014).\n\nThe henequen industry was owned by homogeneous groups called the ‘elites’. They were most often white individuals of Spanish origin who came from two categories: either they were born in Creole families and most often they were already wealthy, or they used the export and import of henequen to create new wealth (Rioux, 2014). In 1856, as a result of reform laws, the lands belonging to the villagers were divided, the ‘elites’ quickly bought land from Mayas and changed that land from subsistence food farming to henequen production. Unfortunately for Maya people, selling their land was the only way to earn some money and support their families (Evans, 2012). However, soon after selling their land most Maya adults became henequen plantation workers. As already mentioned, many ‘elites’ were successful in the henequen industry, but there were 20 to 30 families known as ‘casta divina’ (divine caste), who controlled 80-90% of the henequen industry (Riestra, 1996).\n\nLife on haciendas for workers was very hard. Haciendas became the places in which the Mayas lived, worked and shopped. Maya families often spent their lives on the plantations for many generations (Peniche Rivero, 2003). We use the term ‘henequeneros’ for individuals (often belonging to ‘elites’) that supervised the production of a henequen in a given hacienda and oversaw the Maya families working there. The role of henequeneros was to encourage workers to remain in the hacienda. Also, marriages outside the hacienda were often forbidden. Everything was done to bring families together in order to control the social life of Maya peasants (Joseph, 1982; Remmers, 1981; Wells, 1985).\n\nWorkers were offered loans by henequeneros that were part of the so-called ‘paternalistic goods’ (restriction of the freedom of a person or group of people). This concerned the land of milpa, corn ration, access to water, medical care, and sometimes children’s education. For hacendados (persons who own or supervise haciendas), control over the Maya people provided year-round labor. It was also a certain protection for the workers, but the possible benefits amounted to the loss of autonomy, backbreaking year-round labor, and separation from traditional pueblo life. Thus, henequen workers were essentially slaves as a result of the debt peonage system (an employer compels a worker to pay off a debt with work) (Alston et al., 2009). Even though elites claimed that workers had the right to leave haciendas, realistically, they were accumulating huge debts and were unable to escape. In 1900, rural laborers were spending half to three-quarters of their incomes on basic staples of life, mainly food (Buffington & French, 2000). Their daily food typically consisted of two tortillas, a bowl of beans, and a plate of fish (Sterling, 2012). Although hacienda owners claimed slavery was non-existent, their rules and practices bear strong resemblance to a slave society. The workers were forced to buy food and other things at the hacienda-owned store. The store provided credit, and this indebted the Maya to the hacienda. They were slaves because they could not leave the hacienda until they paid their debt, but they could never do this (Rioux, 2014).\n\nIn Yucatán at this time, education was devoted to the expansion and success of the henequen industry, and as a result, laborers were mainly trained in henequen production only. However, other residents in Yucatán experienced an expansion of education, and secondary and professional education did advance. In 1857, there were 21 public primary schools with less than 2,000 students, but by 1883, there were 225 schools with over 8,000 students. Despite all of the increases in education, many people in Yucatán were illiterate and the literacy rate was still low due to the many laborers on haciendas (Remmers, 1981).\n\nHealth problems and injuries were prevalent on the haciendas, but workers did not have access to medical treatment (Remmers, 1981). Henequen is a rough, spiny plant, and its continued contact with skin often caused irritation and eczema among laborers. The challenging manual labor led to many fractured or broken arms and legs. In addition, carrying henequen leaves in the sun and the heat in Yucatán was especially grueling (Remmers, 1981). Additionally, public health agents ignored hacienda conditions and doctors were rarely present. Despite the modernization efforts in society, healthcare on haciendas was virtually non-existent, so modernity was mainly limited to spaces outside of the hacienda system. Conditions were unsanitary, and diarrhea was the leading cause of death, especially among infants. Poor diets and the lack of sufficient food led to starvation for many laborers, and suicide was not uncommon. Doctors and medicines were only present on larger haciendas, and even then, they were not sufficient to treat the quantity of health issues faced by laborers (Ransom Carty, 2006; Remmers, 1981; Wells, 1985).\n\nLaborers were required to wear specific types of clothing and they were not allowed to wear foreign styles. Also, workers and their families were required to cut their hair a certain way (Moseley, 1980).\n\nThere are many factors that contributed to the decline of the henequen industry, but the changes brought about by the Mexican Revolution were crucial in causing the era of poverty in Yucatán (Evans, 2012; Rioux, 2014). The Mexican Revolution arrived in Yucatán in 1915, five years after it had begun in Mexico City. Laborers experienced slave conditions, and the revolutionaries sought to give them more rights. Between August 1915 and February 1917, the cost of production of henequen fiber increased by more than double due to the increase in wages for workers. These changes were positive for laborers, but henequeneros were forced to pay higher wages and provide more services to the workers. The only reason henequen continued to prosper was the massive demand created by World War I. The further instability in Yucatán and increased prices of henequen encouraged the United States to continue seeking different sources of fiber. However, elites in Yucatán continued to invest only in henequen, which led to an increase in poverty, because henequeneros could no longer pay the workers' debts. After the 1920s, the henequen industry faced continued challenges. The Great Depression continued to affect society, which reduced the demand for wheat and henequen. During the 1930s, adverse weather changes, such as drought, windstorms, cold winters, hot summers, as well as grasshoppers, caused further damage to the wheat industry. Between 1934 and 1940, large areas of land were redistributed, which resulted in the confiscation of 61% of henequen fields. Yucatán became one of the poorest states in Mexico and could not survive without the help of Mexico City (Evans, 2012; Rioux, 2014). During the 1960s, there was an attempt to revive the henequen industry, but hard fiber industries had already been established in other areas, and it would have been very challenging for Yucatán to become competitive in the market again (Carrillo, 2013). However, it should be mentioned here that the Mexican Revolution also brought many positive changes to Yucatán as it ended the slave work conditions and gave more rights to laborers. It also created thousands of schools, health reforms, and sanitation services (Rioux, 2014).\n\nThe women on henequen haciendas had few rights and were under the control of both their husbands and overseers. It was also not uncommon for husbands to beat their wives. While workers were treated like slaves, their wives often experienced the effects of their anger and frustration in the form of violence mainly because of failures in their work. They also worked very rarely in the henequen cultivation, but if they had to work, they were not paid for their work. Thus, the women stayed mostly at home (Wells, 1998).\n\nTheir household responsibilities include preparing food, collecting water and firewood, making hammocks, etc. They were also expected to reproduce to provide for the next generation. Women were also sexually abused. There was a known \"ritual of the first night\" in which a henequenero or overseer rapes the wife or daughter of a worker to show who has the greatest power in the hacienda (Wells, 2006).\n\nThe literature contains much information about Maya life in the second half of the 20th century, including their population size, households, work, income, crops, culture and education (Lutz et al., 2000). It is worth noting that the life of the Maya has not changed significantly since the fall of the henequen economy. However, they were somewhat independent in this time, able to cultivate milpa (corn, beans and squash), usually in small fields, and leave their place of residence looking for work anywhere, e.g. in the nearby holiday resorts of Cancun or Merída.\n\nThe authors of the present paper spent 13 years in Yucatán, mainly at the end of the 20th century, taking part in various research projects which took place in Merida (the capital city of Yucatán), Progreso, Sotuta, Yaxcabá Municipality, and villages near Chichenitza, such as Pisté where the Steggerda research took place (Steggerda, 1932; Steggerda, 1941; Steggerda, 1977). Observations of these communities by the authors has led to the following reflections about living conditions:\n\nThe households (farms) are different, depending on the size of the family and its wealth. Every nuclear family, consisting of parents and at least one child, has its own home. Such a family also has its own or shared garden, kitchen, storage area, and sometimes manufacturing area. The number of shared buildings in a household depends on how many families are living there.\n\nThe Yucatán Peninsula has year-round warm weather and is often hot and the style of home offers a cool place to live. The shape of the houses has been similar from generation to generation. The differences between houses are the size and the materials used to build them. The appearance of the houses also vary depending on the village in which they were located. Many houses are built of wooden stakes (Figure 1 and Figure 2), but there are also houses with a more solid construction. Most houses are about the same size. Often the front door is lined up with a backdoor or window to create cross ventilation, which keeps the home cool. The floors are often concrete and keep the house fresher since the slabs are on the ground. The houses are oval in shape with thatched rooves, which are waterproof when laid in a continuous pattern. Some houses consist of mud and stone walls with thatched roofs, and some are also covered with concrete, grass, or palm leaves (which is very expensive). A thatched roof does not absorb the heat like concrete, so that makes it cooler. Backyards are often full of fruit trees, vegetables, herbs and useful things for the family’s meals. There are also chickens, pigs, ducks, or turkeys.\n\nMost people have two houses. One is for living and the other is for cooking. This prevents the living space from getting smoky or catching fire. The fire is low, surrounded by stones, or against a concrete wall. Most of the cooking is done on a comal for making tortillas or pots for cooking in (Figure 3). Every house contains some type of pottery. The ancient Maya used pottery for cooking, eating, and storing water. The interior furnishing of houses for living is limited mainly to the space needed to hang hammocks used for sleeping. It is not common to store a lot of food in the home. The staple food of corn is mainly kept in the field. Also, Maya houses have no furniture. Necessary items are hung in plastic bags, including food. In recent times, however, refrigerators, TV's and other conveniences have been found there; for example, the authors have often seen a poorly constructed house where there were at least two TV's, a car with an incomplete body and a huge refrigerator.\n\nWomen spend the majority of time not only at home taking care of the children, but also are in charge of gardening and sometimes help men in farm work. Maya women’s dress is very specific and they try to wear it on every occasion (Figure 4). The men take care of the family by mainly cultivating the milpa, hunting and providing other food for the family.\n\nAs previously mentioned, the 20th century included many economic crises, but overall socio-economic conditions improved. These changes are especially interesting when we relate them to the biological status of the Maya Indian populations before the collapse of their high civilization which took place between the 8th or 9th centuries and was probably caused by a combination of deforestation and drought (Stromberg, 2012). The retardation in growth and maturation of Yucatecan populations during the 19th and 20th centuries has been observed (McCullough, 1982; Saul, 1972; Starr, 1902; Steggerda, 1941). There are only two publications on secular changes of body height in the Yucatán. The first one describes the lack of changes in men born between 1860 and 1933 (McCullough, 1982), the second one describes small changes between 1933 and 1956 (Wolański et al., 1994). It should be added that based on skeletal measurements from archaeological excavations from preclassic (2500 BCE-250 CE), classic (250-900 CE) and postclassic (900-1521) periods, and then based on measurements on living people, it can be concluded that Maya Indians experienced a decrease in body height. From the second half of the 19th century to the first half of the 20th century, stabilization of body height was observed. In the last 60 years a slight increase in body height has been observed in children, which affects the final height in adults (Wolański & Siniarska, 1999).\n\nGlobally, Maya people have one of the shortest statures. The average height of contemporary, rural-living Maya men and women in Mexico and Guatemala is 160 cm and 148 cm, respectively (Bogin et al., 2014). Maya adults and children measured in the early to mid–20th century were usually thin, with very low body fat. Short stature and thinness were probably associated with an inadequate diet (Bermudez et al., 2008; Bogin, 2013). Their diet lacked nutrients needed for growth and they also suffered from respiratory and gastrointestinal infections (Bogin, 2013).\n\nOn the basis of the presented characteristics of the Maya living conditions in Yucatan from the beginning of the 20th century to almost the end of the 20th century, the aim of this study is to assess the direction and the level of living condition changes.\n\nThis assessment is built on a comparison of changes in height with age in both sexes, changes in SDI, and changes in women’s age of maturation. Changes in height (secular trend) with the age of the studied individuals indicate how each sex reacts to the living conditions existing in a given period of time. Changes in SDI indicate what are the differences in body height between men and women for each age cohort, which is considered a manifestation of specific living conditions. This index is used in the absence of information on the living conditions of adults at the time of the interview. In addition, one of the many indicators of changes in biological status is the age of maturation. Data on age at menarche will therefore also be considered.\n\n\nMethods\n\nPermission to conduct the study was sought and given by CONACyT (Consejo Nacional de Ciencia y Tecnología). Verbal informed consent was obtained from all participants to participate in the project. Before taking part in the project, the participants were informed of what would be required of them, that participation was voluntary, and that they could withdraw at any time. Verbal consent was obtained over written consent because not all participants taking part in the project were literate. Verbal consent was documented by the project team, and the number of participants that took part or were excluded for various reasons was recorded. The original project protocol included that verbal consent would be obtained, and this mode of consent was therefore permitted by CONACyT.\n\nA cross-sectional study including Merida and vicinity residents (Yucatán, Mexico) was performed.\n\nThe sample included 364 men and 320 women between 20–98 years of age and the study took place from February to November 1994.\n\nEstimating the number of samples was needed to optimize costs of the project. The research was sponsored by CONACyT, the Mexican government agency, and the funds allocated for this purpose were sufficient for the measurements of all volunteers from a given region who agreed to the research. The research was population based and no a priori hypotheses were formulated. It was more about examining the variation of data parameters with age among the Maya. Independently, we tried to have at least 30 people in each study cohort (for each 10-year-old age range and for each gender), which allows us to freely use different statistical tests.\n\nThe research was carried out in 1994, i.e. 27 years ago. Most of the research results have never been published due to the lack of available literature (as in the case of this article). Only the publication of the work by Rioux, 2014 - Honors Theses, allowed the authors to find the relevant literature. Unfortunately, there is no such research in later years in Merida or Yucatan. Some of the existing studies (Bogin, 2013; Bogin et al., 2014), approaching biological status in many aspects, are mainly based on nutritional status, and still do not bring significant changes in the improvement of the living conditions of the Maya group. Why this situation affects Maya is the main goal of this work.\n\nThe concept of this study was to measure people from the most numerous ethnic group of the Merida population. Most of the sample (about 80%) was identified as Maya. The assessment of belonging to the Maya ethnic group was based both on their surnames (two Maya surnames or one Maya surname, as well as on their appearance: short stature, corpulent body structure). Younger individuals worked in different kinds of factories localized in Merida city and vicinity, producing different brands of soft drinks and food products. People surveyed belonged partly to blue-collar workers and were employed to do moderate to heavy physical work (lifting, raising, carrying), while some worked directly on the production line, where the work was monotonous and required a lot of attention. Not only men worked there, but also women. Many women worked in garment factories, built by Americans and for the needs of the American market, which were located in the vicinity of Merida.\n\nOlder people, not working, generally parents or grandparents of people working in factories, were measured in their homes. This research was conducted in two, rather poor, districts of Merida (Chuburna and Cordemex), where many individuals as Maya resided. People of very old age, often living in great poverty, were measured in nursing homes.\n\nWhen examining more educated people who held an executive position or supervised the work of other people, these data were not included in the final research material.\n\nEducation level varied from illiterate to those who had not completed secondary school. Income levels varied between 900 NP (new pesos/month) for younger people to 300 NP/Mo for older people at a time before the economic crisis at the end of 1994 when the value of the peso was 1US$ = 3.4 P.\n\nThe sample was divided into six age groups by gender: 20–29, 30–39, 40–49, 50–59, 60–69 and 70+ years.\n\nBody height of both men and women were collected, as well as age at menarche for women. The height measurement was performed by persons trained and employed to carry out this research. The same was true for age of maturation questions.\n\nThree phenomena were considered: secular trend in height observed in the cohorts of men and women, sexual dimorphism in height which was useful for the assessment of living conditions for the population studied, and age at menarche.\n\nThe secular trend of body height was presented and adjusted for age-associated stature loss after the age of 30 years (0.06 cm / yr) according to Trotter & Gleser (1951).\n\nSexual dimorphism in height was interpreted using the SDI, which was calculated by the following formula: (X¯Males - X¯Females / X¯Females) * 100. It has been widely described in earlier publications (Antoszewska & Wolański, 1992; Siniarska, 1996; Wolański, 2012; Wolański & Kasprzak, 1976).\n\nAge at menarche changes between 10-year-old women’s cohorts were assessed using the Kruskal-Wallis Test.\n\nAll calculations were done in Statistica 13.0 (Dell Inc, 2016).\n\n\nResults\n\nOur results showed that the body height of men and women declines with increasing age (Table 1). The effect of age and secular trend on body height of adults was assessed using regression analysis of height and height corrected for the effect of aging after 30 years of age on the year of birth (Trotter & Gleser (1951) prediction of the aging process (0.06 cm per year) was used). The results indicate that height adjustment for the effect of aging does not show significant secular trend in men, but these changes are significant in women (Table 2). However, the large difference in height between the 75 and 55 age cohorts (almost 14 and 13 cm, respectively) may be due to osteoporosis in women. These findings emphasize that secular trend in Merida sample is lower in men than in women.\n\n1 Adjusted for age-associated stature loss after the age of 30 years (0.06 cm/yr) after Trotter & Gleser (1951)\n\nConsidering the SDI results for each of the age group, significant changes in the index values from 9.9 to 7.6 were observed. This may indicate a constant, but very small improvement of living conditions, in the time interval examined (Table 3).\n\nThe age at menarche of women did not show statistically significant acceleration with age (Table 4, Figure 5).\n\n\nDiscussion\n\nThe results of these studies are based on the height data for female and male cohorts analyzed at 10-year intervals, on SDI data assessing living conditions, and also taking into account the age of women maturation evaluated by age at menarche.\n\nThe found secular trend in height (younger 10-year cohorts are slightly taller than the older ones) and the applied correction for changes related to aging indicate that among female differences in height between age cohorts are much more pronounced than among men. If age related changes are eliminated, the secular trend of 0.25 cm per decade in men in Merida, which is not statistically significant, is seen. In Merida women, it is 0.90 cm per decade, which is statistically significant. These findings emphasize that age changes in height in Merida are lower in men and greater in women.\n\nTo understand this phenomenon, the SDI was calculated, and its magnitude explains the prevailing life conditions at the time of each six intervals. The calculation of sexual dimorphism, in the absence of socio-economic data, is still used in the assessment of the prevailing living conditions. Here, we describe a second model, which is based on an approach published by Bogin et al. (2017) and assesses sexual dimorphism of height in relation to three economic predictors: (1) gross domestic product; (2) gross national income per capita adjusted for personal purchasing power; and (3) the relative degree of income distribution adjusted for health inequalities within a nation and calculated by the Wagstaff method (Gini coefficient). In the previous study by Bogin et al (2017), sexual dimorphism in adult height was calculated for 169 countries and its average value was 11.8 cm (sd 2.0). The variation is considerable and there is a significant positive association for greater sexual dimorphism with increasing height for both men and women. Therefore, it could be concluded that sexual dimorphism in adult height is more affected by its changes in males than females (Bogin et al., 2017). Table 5 shows the interpretation of sexual dimorphism based on three predictors in Bogin et al’s study.\n\nThis second model could not be applied on our studied Mayan population, due to the lack of detailed information on the three economic predictors. However, the two models (SDI as used by the authors and the model proposed by Bogin et al., 2017) of the assessment of the impact of living conditions on the body height of Maya men and women show that low or high values of sexual dimorphism may indicate improvement or worsening of living conditions (Bogin et al., 2017; Wolański & Kasprzak, 1976).\n\nWhat are the changes in height if we compare both sexes? Body height has increased dramatically during the 20th century in many populations across the world with only few exceptions. This visible trend started at least in the mid-19th century (Cole, 2003). These changes are also related to body weight and their direction depends on environmental conditions (including mainly living conditions), which can deteriorate or improve. It should be noted, however, that changes in body height occurs first in men and then in women and are slightly weaker in women. This is due to greater sensitivity to environmental factors of men than women (Bogin, 1999; Cole, 2003; Kaczmarek & Wolański, 2018; Mamidi et al., 2011; Özer, 2007; Singh-Manoux et al., 2010; Tutkuviene, 2005; Wolański, 2012). In addition, previous studies also looked at some physiological variables, including respiratory variables, and showed a greater relationship between these variables in women then in men, which confirms that women are less sensitive to environmental factors (Siniarska, 2000).\n\nDespite the improvement in living conditions among Maya women, there were no changes in the age of menarche over the 20th century. However, the most recent study, conducted in 2011–2014, showed that in a 33-year-old Maya women menarche occurred at 12.05 years (Azcorra et al., 2018), which is much earlier than observed in a 25-year-old Maya women examined in 1994 (12.42 years; in our study). This may indicate a recent improvement in the living conditions of Maya women in Yucatán but it may also depend on the female cohort taken for the study, which is not as numerous as in the case of this material, as well as may relate to another socio-economic group.\n\nThe Maya social and living conditions are also evaluated through research on children and youth in Merida (the capital of the Yucatán state), carried out in 1996–99 (Siniarska et al., 2019). It is assumed that there are three ethnic groups in the Yucatán: the Maya, the Mestizo and the Creole. Ethnic groups were established using two surnames of children from the father’s and mother’s side. Maya (two Maya surnames), Mestizo (one Maya and one Creole surnames), and Creole (two Creole surnames) (Siniarska, 1999; Wolański & Siniarska, 1999). Because there were not statistically significant differences between children from Maya and Mestizo groups in most somatic measurements, those two ethnic groups were joined together and the final comparison was done between Creole and Maya / Mestizo groups. The results of these studies indicate that Maya / Mestizo children and youth are shorter, with shorter legs and are characterized by relatively longer upper limbs than legs and relatively (to height) wider shoulders as compared to their peers from the Creole group. Ethnicity was the main effect factor for leg length both in boys and girls, and for the body proportions: upper-to-lower limb in girls and shoulder-to-body height in boys. It may be stated that variation in body physique and body proportions during the postnatal growth in different ethnic groups is under the influence of complex interaction between genetic and environmental factors (Siniarska et al., 2019). This work was continued using the same type of three-ethnic division by Azcorra et al., 2013.\n\nHowever, further research, especially that carried out by Fernández del Valle (2011) from 1986 to 2000, showed a different relationship between the Maya and the Creoles. The question arose as to whether researchers were paying careful attention to the ethnic division based on surnames. Is the division that two Spanish surnames mean Creoles, two Maya surnames mean- Mayas, and mixed surnames -mean Mestizos, correct? As it turns out, this division is not fully correct. We have to remember that in the turn of the century (the 19th and 20th) in some places of Maya land (especially in Yucatán), Maya inhabiting communities were under supervision of owners of sisal or other plantations' haciendas and Maya people received the surname of the owner (as a gift). It is the case of a small Maya community Dzeal located near Pisté (Yucatán Peninsula) investigated in 1986 and 2000 (Fernández del Valle, 2011). The people of Merida, participating in various types of research within ethnic groups, distinguish the Maya mainly by their appearance.\n\nReturning to the results of this work, which includes adults, the observed differences in the secular changes of men and women in the Maya population since the beginning of the 20th century are most likely caused by living conditions. The very poor living conditions of Mayas began in the colonial period (19th century), where large haciendas (mostly sisal plantations) existed in the Yucatán Peninsula (EY, 1980; González Navarro, 1979) and continued until the end of the Mexican Revolution (around 1940), when the living conditions of Mayas slightly improved (Evans, 2012; Rioux, 2014). At that time the mortality rate for women was higher than that for men. Men who physically worked on the plantations were under health care by the hacienda owners, but women's health was not a priority. This fact could have worked as a selection mechanism within the cohort of women. There was a high mortality rate of women and men often had a series of wives (personal communication with Dr Gilberto Balam-Pereira, Cinvestav Mérida, 2000).\n\nWomen on henequen haciendas had very few rights and were under the control of both their husbands and their husbands’ overseers. It is not uncommon for workers to beat their wives because of failures at work. While laborers were treated like slaves, it has been reported that their wives often experienced the effects of their anger and frustration in the form of violence (Wells, 2006). Women had less mobility than their husbands and remained mainly in the home performing many household chores (food preparation, retrieving water and firewood, making hammocks etc.). It was also very rare for women to work with the henequen crop, but if there was a need, they were not paid for their work (Wells, 1998). They were also expected to reproduce to create another generation. Women were also subject to the sexual impulses of men: there was the so-called “ritual of the first night”, in which henequenero or overseers violate a wife or daughter of a laborer to show who has the greatest power in the hacienda (Wells, 2006).\n\nA question can be asked what Maya women themselves think about the changes in their lives. The authors of this work, during a long stay in Yucatán in 1992-2005, had many contacts with various families, especially in the villages of Yaxcabá Municipality. Many research projects took place in these villages, which involved renting apartments and ordering food from the local families. The authors were in close contact with certain families, which made it possible to have very personal conversations. We made a few observations: the Mayas did not want to open bank accounts, and even in the case of significant savings, they did not want to modernize their homes; money was collected in case of the husband or son's illness (illness in daughters was not alluded to); modern appliances were not required, e.g. buckets of water were used for washing and showers were not regarded as needed. Of course, it is a matter of time when they will change their lifestyle, especially due to younger generations.\n\nAgainst the background of the characteristics of the life of Maya women at the turn of the 19th and 20th centuries, it can be seen that their situation has improved over the years. Maya women from the end of the 20th century are treated much better. However, the life of men was better than women at the beginning of 20th century. It is expected that the living conditions of Maya men did not improve significantly in the 20th century. This could be the most important reason showing the observed secular trend of increasing height is less in men compared to women.\n\n\nConclusion\n\nThe Maya living conditions throughout the late 19th century and the first half of the 20th century were very bad. This was due to the cultivation of henequen fiber, which was led by ‘elites’, primarily white individuals of Spanish origin, named henequeneros. They bought land belonging to Mayas and turned it into haciendas (large agricultural estates or plantations) producing henequen. After selling their land, most Maya adults became henequen plantation laborers. Haciendas became the places in which Mayas lived, worked and did shopping. Laborers were offered loans by henequeneros as part of the so-called ‘paternalistic goods’ relating to the land of milpa, corn ration, access to water, medical care, and sometimes children’s education. Even though the ‘elites’ claimed that workers had the right to leave haciendas, realistically, they were accumulating huge debts and were unable to escape. In other words, henequen workers were essentially slaves as a result of the debt peonage system. Finally, Mayas became strongly associated with working on henequen in haciendas and because the loans could not be repaid, they had to stay with entire families in the workplace. All members of the Maya families suffered, but women were particularly affected. The production of henequen in haciendas was based on the labor of men. Poor diets and the lack of sufficient food led to starvation for many laborers, and suicide was not uncommon. In case of the laborer’s disease, it happened that the owner of the hacienda looked after him in his home, but the sick women were not looked after. If women had to replace men in henequen production, they were not paid for it. The main role of Maya women was to run the house and give birth to children. They suffered physically not only from their husbands who were reported to be violent towards their wives, but also from the owners of haciendas who were reported to humiliate and rape both the wives and daughters of their workers on various occasions. After the Mexican Revolution, the whole industry related to the production of henequen, which ceased to be \"Yucatán gold\", collapsed, but the living conditions of Mayas have since improved.\n\nWe showed that the changes in living conditions were not as significant for men as for women. Until the end of the 20th century, height of men increased a little, but the changes are not statistically significant, while it increased statistically in the case of women. There has been no change in the maturation time of Maya women throughout the 20th century, but recent research in the early 21th century shows that there has been little progress (earlier maturation assessed by age at menarche). The way of thinking of Maya women, with whom there was direct contact in the late 20th century, was focused mainly on taking care of their husbands and sons, they did not respond to questions about the future of their daughters. They still accepted ‘superiority’ and better health care for their husbands and sons compared to them and their daughters. This may be a result of the mistreatment of women over many generations. However, it is to be hoped that the quality of life of Maya women will quickly improve significantly due to the widespread fight for women's rights and the protection of these rights.\n\n\nData availability\n\nFigshare: Merida1994-95.csv, https://doi.org/10.6084/m9.figshare.16447350.v1 (Siniarska & Wolański, 2021).\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": "96803",
"date": "25 Oct 2021",
"name": "Maciej Henneberg",
"expertise": [
"Reviewer Expertise Science",
"Biology",
"Anatomy",
"Biological Anthropology",
"Applied Mathematics"
],
"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 presents valuable data on Maya people. The introduction, though historically interesting, is too long for a paper exploring just two biological characteristics. Many human biologists today may not know what the henequen is. A sentence explaining that it is a source of industrially useful fibre would be useful. The Discussion repeats one paragraph from the Introduction. The Conclusion, that is actually an extensive Summary of the whole paper, instead of a short statement of what is the new addition to knowledge, repeats a lot of Introduction. Too much history, compared to biology.\nThe main problem regards data collection and analysis. In the description of how data were collected the authors state that membership of the Mayan group was established, among other criteria, also on the physical appearance of being short. This, in a study of stature changes, leads to the circular reasoning. Please explain more precisely your \"ethnic\" classification. The authors correctly state that stature loss with age must be corrected for before comparing body heights of people born in different years in order to draw conclusions about secular trends. They use a linear correction for loss of statue with age of some 0.6 mm per year. This, however published by Trotter and Gleser in 1951, has been superseeded by the findings that, as most biological processes do, decline of stature with age is curvilinear, described by the second order polynomial regression (see examples of papers cited below). This means the decline speeds up with age. My perusal of numbers contained in the Table 1 indicates that such curvilinear decline is the case among Mayans. Secular trends in stature, and other biological characteristics, do not follow straight lines, either. Therefore linear regressions of stature on age shown in Table 2 may be an insufficient approximation of actual trends, especially if corrections for age were too simplistic.\nFinding no secular increase of stature, at least in Mayan males, is not surprising to I who found no increase on two different continents of the Southern Hemisphere. The lack of secular trends is more common than expressed in the literature because of the tendency not to publish \"negative\" results.\n\nThe lack of change of the menarcheal age disagrees with the significant trend in Mayan females' stature. I understand, of course, that the method of establishing the menarcheal age of these women was a recall rather than probit analysis. The recall method, though I defended its accuracy in some of my research situations, is prone to subjective memory and satus errors that may vary with age. Menarcheal ages in Table 4, though consistent with some published menarcheal age , are fairly young, especially for women who lived in poor conditions. For instance, girls in families of rural labourers (situation similar to henequen plantation workers) in Africa in 1990s had probit menarcheal age a bit over 14 years. Young menearcheal age of Mayans needs an explanation in the Discussion.\nThere are a few minor grammatical errors in the text. These can be easily eliminated by careful editing. One common problem we all have these days is sex as the English expression evolves. The authors study gender differences by calculating the sexual dimorphism index and in the text use both \"gender\" and \"sex\". The standard understanding in human biology is that \"sex\" is what is given by XY chromosomes and expressed anatomically, while \"gender\" is what a person chooses to be socially. \"Poilitical correctness\" pressures authors into use of \"more polite\" expressions. Sex, of course seems to be less polite. I respect the authors' right to be politically correct, but then they should use the Gender Dimorphism Index and remove all mentions of sex from the text.\nTable 5 can easily be reduced to a few lines of text.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/10-1034
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https://f1000research.com/articles/10-672/v1
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28 Jul 21
|
{
"type": "Research Article",
"title": "The indigenous meaning of dysmenorrhea: using modified photovoice to document perspectives of traditional health practitioners (THPs) and indigenous knowledge holders (IKHs)",
"authors": [
"Melitah Molatelo Rasweswe",
"Mmapheko Doriccah Peu",
"Fhumulani Mavis Mulaudzi",
"Mmapheko Doriccah Peu",
"Fhumulani Mavis Mulaudzi"
],
"abstract": "Background: Globally, health understanding and beliefs vary across sub-cultural groups, depending on geographical location. Increasingly, various parts of the world recognize these perspectives to offer culturally sensitive healthcare services at primary level. Understanding the indigenous perspectives of dysmenorrhea meaning from the custodians of knowledge holders may add to the value of literature that may be used to advocate humanized culturally sensitive healthcare. This article aimed to explore and describe the perspectives regarding the meaning of indigenous dysmenorrhea among Batlokwa traditional health practitioners (THPs) and indigenous knowledge holders (IKHs). Methods: A qualitative, explorative study with a modified photovoice design, which included photographs, interviews and lekgotla discussion was employed to engage THPs and IKHs residing in Botlokwa Limpopo province, South Africa. Initially, a purposive sampling technique was used to select the participants, followed by snowball sampling. The participants themselves analyzed the photographs and described their meaning during individual interview using the acronym “PHOTO”. The researchers employed thematic analysis of interviews and Lekgotla discussion, in which themes were identified, formulated and analyzed from the codified data set. Results: In total, eight women participated in the photovoice study. The findings showed that indigenous understanding of dysmenorrhea stems from the African belief about health and illness with special emphasis on importance of holistic meaning. To the THPs and IKHs dysmenorrhea was a broad and integrated trend of a normal or abnormal process of illness that occurs periodically during menstruation. Conclusions: The THP’s and IKH’s indigenous meaning of dysmenorrhea reflects physical, mental, emotional, social, environmental, political and economic dimensions. Therefore, dysmenorrhea should be understood from a holistic approach. With appropriate partnerships and processes in place, this knowledge may be well represented in dominant healthcare systems and health research.",
"keywords": [
"Dysmenorrhea",
"Indigenous",
"Indigenous Knowledge Holders",
"Lekgotla discussion",
"Photovoice",
"Traditional Health Practitioners",
"South Africa"
],
"content": "Introduction\n\nDysmenorrhea has been the focus of global public health efforts for many years now. Dysmenorrhea is common among women of reproductive age including adolescents and it is known to be the cause of pelvic pain during menstruation.1 Although researchers have reported a general stabilization in the management of dysmenorrhea, it continues to affect a large number of women. A literature view conducted in 2016 to better understand the epidemiology of dysmenorrhea and its effect on public health in different countries revealed that the prevalence of dysmenorrhea varied from 34% to 94% depending on the country.2 A survey that investigated the prevalence of menstrual disorders and its impact amongst Tshivenda speaking teenagers in rural South Africa reported that 61.27% of teenagers suffer from dysmenorrhea and 56.4% experience severe abdominal pains during menstruation.3 Although dysmenorrhea is a universal burden, the meanings and practices are different from culture to culture and society to society. However, the primary focus of understanding dysmenorrhea and interventions in this regard have been on Western ways. Indigenous meanings and healthcare are consistently identified as less likely to make sense. The indigenous meanings and healthcare system involve cultural health promotion, prevention of illness, treatment, and rehabilitation, it differs from the Western health system in its integral and holistic approach. Many communities, in South Africa had their own well-developed indigenous knowledge health systems that positively enhance the understanding of illnesses such as dysmenorrhea. Indigenous knowledge has a significant influence in health-related beliefs and practices.4 This knowledge forms an integral part of the health care history in South Africa.5 The Protection, Promotion, Development and Management of Indigenous Knowledge Act 6 of 2019 in South Africa provide access of this knowledge to indigenous communities.\n\nAmong those who have knowledge of indigenous healthcare in South Africa are traditional health practitioners (THPs) and indigenous knowledge holders (IKHs). The THPs and IKHs are commonly known to be the custodian holders of indigenous knowledge. They also have a particular value of wisdom and influence in issues that are of indigenous health care.6 Accordingly, they are commonly consulted privately to establish the origins of illnesses and prediction of treatment success, especially as a first line of care or when western medicine is failing.\n\nIt can be argued that the multicultural beliefs and practices make it necessary to explore and understand the perspectives in dysmenorrhea meaning, as it might offer insights that have been neglected by the Western health care system. Understanding indigenous perspectives of dysmenorrhea meaning from its practitioners is a high priority for individuals, communities, healthcare systems and government because it might provide effective ways to deal with illnesses and health promotion at the primary healthcare level. Moreover, the National Department of Health (NDoH) in South Africa has taken firm steps in transforming and recognizing indigenous health since the end of apartheid.7 Currently few studies have explored the indigenous perspectives of dysmenorrhea.8–10 Further, none of the studies have provided comprehensive information on the indigenous meaning of dysmenorrhea in which THPs and IKHs as indigenous knowers were co-researchers. Thus, women who prefer indigenous knowledge health systems can experience barriers in receiving this care if it not known and documented. A study conducted in 2017 indicated that a lack of knowledge and acceptance of indigenous healthcare disadvantages many people from accessing culturally sensitive healthcare.11\n\nDeveloping understanding and acknowledging dysmenorrhea meaning from the perspectives of Batlokwa THPs and IKHs has the potential to serve as a basis for future research. This in return may lead to formulation of partnerships with indigenous health practitioners, and may contribute to development of strategies, protocols, processes, and cultural appropriate intervention programs to improve women’s health services. Therefore, the purpose of our study was to better understand and document indigenous perspectives of dysmenorrhea meaning among Batlokwa THPs and IKHs.\n\n\nMethods\n\nQualitative research using a photovoice design was used to gather and explore the social and personal meanings that Batlokwa THPs and IKHs ascribe to dysmenorrhea. Photovoice is a qualitative method to be used within community based participatory research.12 It positions participants as co-researchers since they are involved in taking photographs and making sense out of them. It is also of value when the issue under study is sensitive and involves vulnerable groups such as indigenous or traditional women. Photovoice entails the participants taking photographs, assign meanings to their photographs during individual interviews and/or group discussions. Participants become directors or coresearchers and speak through photography.13,14\n\nThe research was conducted in Botlokwa a small village located in Limpopo province, South Africa. The village primarily consists of the Blacks, dominated by the Batlokwa ethnicity group. The recruitment was done through the local authority gatherings, placing posters in public areas and presentations in women gatherings. Eligibility criteria included 18 years and above Black women, Batlokwa ethnicity group, residing in Ga-Ramokgopa village Limpopo province, known in the community as THPs or IKHs. The study excluded all the women who were still undergoing training to be THPs and the THPs that are from other regions, provinces, and foreign countries.\n\nThe first step in the sampling was to purposively select the women who contacted the researcher and agreed to participate in the study. The snowball technique was used to further identify potential participants through the informed network and recommendation of the women who were already recruited by the researcher. They directed the researcher to others whom they knew and trusted as genuine IKHs of dysmenorrhea and treatment modalities. This referral process continued until the researchers had reach sample size of 15 participants who showed interest in the study and met inclusion criteria. However, three did not come for the photovoice training session and four did not hand back cameras and photographs even after several reminders. Therefore, only eight THPs and IKHs took part. The size of the study sample was estimated based on the fact that 7 to 10 participants are ideal group size for any photovoice study to allow practical ease and in-depth discussion. The main reason for using both purposive and snowball sampling was that the number of IKHs in South Africa is not known. In addition, to gain access to their knowledge one has to rely on those who consented to assure others that the study meant no harm to their knowledge.\n\nData was collected through photographs, individual interviews and lekgotla discussion and lasted for 6 months between May and November 2018. Four stages of photovoice were followed; First session was a brainstorming and photograph taking training, which took place with individual participant in their own homes until they are competent The session was to familiarize the participants with the research topic, reasons for the study and photograph taking technique; 2): Taking photographs – When the researcher was satisfied that the participant could use and was able to take photographs, each was handed a 27-exposure disposal camera. Thereafter, the researcher revised the usage instructions with the participant. The participants were then directed to take pictures of anything related to indigenous perspectives of dysmenorrhea for four weeks. For example, environment, objects, symbols, plants, people. They were advised to refer to the guiding questions when choosing things to photograph, to avoid taking photos of people without their consent, and hide people’s faces; 3): Individual interviews – To attach meaning to own captured photographs, a principal researcher (MMR), who is a female, Nurse lecturer and PhD student conducted individual interviews in different settings convenient to participants. Most participants preferred their own homes. A female research assistant (psychologist and PhD student), helped in taking field notes. Both principal researcher and research assistant were experienced in conducting individual interviews, maintaining confidentiality for the research study, and interested in women’s health. Interviews lasted 40 to 120 minutes and audio recorded only if the participant gave consent. Each interview was guided by questioning acronym “PHOTO”.15 which made questions to be consistent in meaning across 8 participants without follow-up interviews; 4) Lekgotla discussion – One lekgotla discussion which is an open forum in which indigenous community members in Sub-Saharan Africa use to debate and reach agreements on raised issues16 was conducted with same eight participants and a research assistant. The discussion lasted for five hours and was audio recorded. Field notes were also taken. All study materials can be found as extended data.37\n\nEthical approval to conduct the study was obtained from the university of Pretoria, faculty of health Ethics Committee, Ref 20/2018. Permission from local authority leadership was obtained in order to affirm the relevance of the current research and to ensure that the research was conducted in ways appropriate to local customs. In addition, the participants provided written informed consent prior to taking part in the study.\n\nData analysis was done concurrently with individual interviews. During the interviews the photographs acted as “codes” that represented the participants’ perspective descriptions of dysmenorrhea. No software was used to analyze data. Analysis of the individual photographs was left solely at the discretion of the participants during individual interviews, guided by questioning the acronym “PHOTO”.15\n\n• What is in this photo related to indigenous meaning of dysmenorrhea/describe the activities on dysmenorrhea in this photo?\n\n• What is happening in this photo related to indigenous meaning of dysmenorrhea knowledge?\n\n• How does a photo of this object link to indigenous meaning of dysmenorrhea?\n\n• What does this photo tell us about indigenous meaning of dysmenorrhea?\n\n• How does this photo provide opportunities to understand indigenous dysmenorrhea?\n\nWhen analyzing photographs, participants used words to explain further and effectively communicate their thoughts, and to stimulate discussion among themselves and the researcher. The researcher was guided by the information provided by the participants to ask more questions. After each individual interview, the principal researcher manually documented the emerging ideas from the narratives and stories recorded alongside the notetaking in a table created to organize and manage data. Thereafter, the ideas were compared and synthesized to form themes and sub-themes.\n\nDuring Lekgotla discussion, all the photographs discussed during individual interviews were re-analyzed again with all the participants present to confirm and identify more themes and gaps. Analysis of the photographs as data involved the group discussing possible meanings, referring to the research question. The researchers and participants reviewed photographs and stories to assess the congruency between the two and contextualize selected photographs by providing details and meaning of the photographs alongside their stories in relation to the Batlokwa cultural beliefs and practices. The significant statements identified regarding dysmenorrhea were listed and grouped according to similarities in patterns of ideas and associations. In the process, the participants chose the photographs that best represented the main themes. Thereafter, it was discussed how these photographs may contribute to the knowledge of indigenous dysmenorrhea among the Batlokwa ethnicity.\n\nThe researcher clustered all the selected photographs (24) into various groups, according to what was seen on the photograph, such as plants, animals, environment, person, and other objects. This exercise formed unique clusters with overlapping groups of associations that helped the researcher to develop, connect and discuss themes from the photographs to form the indigenous perspectives of the dysmenorrhea meaning among Batlokwa women. In addition, all authors examined photographs and attached meanings extracted from the interview transcripts to confirm themes related to dysmenorrhea meaning. Thus, audio recordings and field notes assisted in identifying keywords and phrases related to indigenous perspectives of dysmenorrhea meanings. Thereafter, the researchers classified IKHs and THPs photos and context according to concepts identified in the individual interviews and modified Lekgotla discussion. The understanding was compiled into a report and given to the participants for review prior to dissemination.\n\n\nResults\n\nWomen were the central participants in this study. The total number of women who participated were 08. Their ages were between 28 and 89 years old. They all have indigenous knowledge in treating dysmenorrhea at Botlokwa village, Limpopo Province. Three of the women were trained THPs, and five of them acquired indigenous knowledge through oral translation and observation either from the elders in the family or community or when they were treated for dysmenorrhea. Table 1 outlines the demographic data of the participants.\n\nThe data produced were rich descriptions and narratives that were oral and visual. The central theme that emerged strongly was holistic understanding of dysmenorrhea meaning and was associated to process or journey connected to women health, the description further grouped women’s health issues together. The findings showed that the participants of Batlokwa ethnicity had their own point of view towards the meaning of dysmenorrhea, which is influenced by their cultural orientation.\n\nThe presented photographs and meanings attached revealed that Batlokwa women understand dysmenorrhea as a holistic illness. Dysmenorrhea is understood as not only a physical illness, but interdependent with mental, emotional, spiritual, social, economic, and environmental factors.\n\nParticipant #3: “selumi” (dysmenorrhea) means that mind, body, emotion, spirit and environment are not balancing”.\n\nParticipant #6: “Dysmenorrhea is addressed within a holistic approach, we consider emotional, mental, spiritual, including the environment in which the woman comes from”.\n\nParticipant #8: “It is women reproductive system illness affecting body, mind, spirit, because our ways of healing looks holistically at the body, mind and spirit”.\n\nIn terms of dysmenorrhea as a process or journey, a photograph (Figure 1) was presented, which was interpreted as embarking on the health journey, but interrupted and distracted by physical and emotional pain throughout reproductive age or as a process that occurs over some time in the women’s’ lives. Participant #6: “dysmenorrhea builds up with time, other parts of the women reproductive system are affected”. Participant #2: “when experiencing dysmenorrhea, we think of how long the person has being in this journey because symptoms increase with time”.\n\nDrawing from Figure 1, participant #1 said “selumi ke leeto le bohloko!!!” (dysmenorrhea is a painful journey!!!), “poor woman is looking forward for the menstruation every month in preparation for falling pregnant, then what supposed to be a pleasant journey turn out to be a suffering”.\n\nParticipant #7: “Some of the women walk this road every month, taking a very painful journey for the sake of womanhood”\n\nIn the lekgotla discussion the participants debated on how the process or journey of dysmenorrhea affects women emotionally. Participant #7: “being unable to perform house chores because of “selumi” is depressing”. Participant #3: “thinking of the stigma attached to “selumi”, been labelled with names such as “moopa” (barren) really affects women emotionally”.\n\nOn the other side, women talked about the process of dysmenorrhea in terms of it reoccurring. Participant #8: “Well, “selumi” is a process, it reoccurs if not treated well. If not treated, it will remain a monthly journey”. Participant #5: “It continues throughout the reproductive age if not properly treated”.\n\nOn the other vein, meaning of dysmenorrhea was influenced by the women reproductive system makeup. They viewed dysmenorrhea as inclusive to all other reproductive health issues. Figure 2, a chain, emphasizes the connection of a women’s reproductive system. It conveys a strong sense of why and how dysmenorrhea is connected to other reproductive organs and connected to other women’s health issues. The arguments seemed to be rooted in cultural beliefs and practices.\n\nParticipant #2: “I check the whole reproductive system to identify the root of dysmenorrhea including infertility”.\n\nParticipant #6: “With “selumi”, it means somehow the whole reproductive system is affected”.\n\nParticipant #8: “I think “selumi” eats up the lining of the uterus. It affects the whole reproductive system because the whole abdomen and back will be painful”.\n\nMetaphors of bridges and messengers were also used to better understand grouping of women’s health issues.\n\nThe findings revealed that dysmenorrhea is not just a pain; it is seen as the bridge (Figure 3), linking the sufferer to other chronic pain conditions associated with woman’s reproductive system problems.\n\nParticipant #1: “Dysmenorrheal pain is not only from menstruation; it is linked to other women illnesses”.\n\nParticipant #5: “bridge emphasizes the connection between dysmenorrhea and other women’s health issues to reinforce holistic meaning”.\n\nParticipant #6: “The symbol of a bridge means move to the other side of reproductive system”.\n\nThe pain of dysmenorrhea was regarded as a message informing that there is something wrong with the woman’s reproductive system. They explained that dysmenorrhea is a message that the woman will be infertile in future or is already infertile. The logic here was that dysmenorrhea sends the message to the woman and family to seek help and correct complications of infertility early. The following phrases were extracted from the discussions: “inability to have children”, “unable to fall pregnant”, “will not have children”, “childless”, and “moopa” meaning barren (Participants #3, #7, #8).\n\nThe participants' expressions of dysmenorrhea as a messenger for infertility were based on the following arguments: Participant #5: “Indigenously when we treat women for dysmenorrhea, within a month or so the woman will fall pregnant, that’s how we discovered that dysmenorrhea was just a sign for infertility”.\n\nParticipant #4: “Look … a woman will present with pain during menstruation, but when you do divination check (consulting ancestors), you find many reproductive health problems that are linked and related to what she is complaining about … and all will complicate to infertility”.\n\nA couple of women talked about “selumi” being related to blocked fallopian tubes, sores in the womb (disturbing implantation), and untreated sexually transmitted infections. They believed that if all of these are not adequately treated, a sufferer would not fall pregnant. For instance, a photograph of a chained and locked padlock was presented and analyzed as a message that a woman is blocked from conceiving a baby (Figure 4). A knotted robe (Figure 5) was also presented as blocked tubes (noga e bofile).\n\n\nDiscussion\n\nThis paper offers insight into the indigenous meaning of dysmenorrhea from THPs and IKHs. The findings of this study support the notion that health beliefs and practices vary across countries, sub-cultural groups, and geographical location.17 Therefore, socio-cultural factors influence on how people understand their health issues and on how to treat them. Analysis of the photographs explored similarities and differences between objects or people portrayed by the participants and complemented the interviews and thematic analysis.18 In a traditional Batlokwa ethnicity, THPs and IKHs understood dysmenorrhea as a holistic illness. During meaning-making, they used metaphors of process and journey to conceptualize dysmenorrhea as an illness that results from a woman reproductive system but show during menstruation. They also related and grouped dysmenorrhea with other gynecological problems.\n\nHolistic understanding means that dysmenorrhea does not affect the physical being only, but also affects the emotional, spiritual, cultural wellbeing of the whole community and the environment.19 The photographs taken were of woman carrying luggage, chains, padlocks, bridge and knotted robes. These photographs were to serve as visual descriptions, to back up the discussion on dysmenorrhea meaning. Connection of all these photographs and discussions were found essential in creating a relationship when making meaning of dysmenorrhea as a holistic illness. Physical symptoms of dysmenorrhea were connected to emotions, spirituality, culture, and the relationships they have with the land and centered on their belief that there should be harmony between all the elements.20 Notably, disharmony between the elements was understood as the cause of dysmenorrhea. Moreover, they argued that when one element is affected, care should be extended to the other elements (holistic) to re-establish harmony. The findings further, showed that although symptoms of dysmenorrhea are predominantly physical, Batlokwa are not content with the physical illness of the body only but include emotions and spirit. The relationship, therefore, between the physical, emotional and spiritual elements can be determined to nurture and benefit each other within the cultural environment to understand dysmenorrhea from holistic perspective.19,20 Thus, indigenous people often view illnesses from a holistic perspective that includes spiritual, mental, emotional, and physical health.21\n\nOf more value is that, the Batlokwa’s holistic understanding of dysmenorrhea has elements of primary health care as stipulated.22 The Batlokwa THPs and IKHs’ principles of understanding dysmenorrhea holistically provided practical guidance in the management of menstrual and gynecological health problems in a holistic approach.8 This put THPs and IKHs in a unique position to understand and heal the illness of their patients because they have a thorough knowledge and understanding of the history of their patients and they also share similar customs and beliefs. A holistic understanding of dysmenorrhea may also assist health care practitioners in both indigenous and Western worldviews with a conceptual base when diagnosing, treating and preventing dysmenorrhea and other women’s health illnesses. Indigenous understanding of health and illness is complex; as such, it is necessary to be holistic when making meaning of illnesses. Therefore, this suggests that a holistic understanding of dysmenorrhea should be prevalent in efforts aimed at improving the health of individual women experiencing dysmenorrhea and preventing dysmenorrhea within the rural communities.\n\nTo emphasize on the point of holistic meaning, the metaphor of process and journey was used to make meaning of dysmenorrhea; at the same time, the participants connected dysmenorrhea to other gynecological problems to approach it holistically. The description of a photograph in Figure 1 revealed that a meaningful dysmenorrhea concept was made using a metaphor of a process and journey. These metaphors were used to understand dysmenorrhea holistically. This does not mean that the contextual and basic meanings of dysmenorrhea are literally a processes and journeys in which women partake. It is merely a comparison. A journey points out a road that one travels on, while process times out and measures the period that one travels the road of the illness and the luggage (struggles or battles) carried through the journey. The use of metaphors was found to assist in adding clarity and depth of illness meaning rather than presenting factual information of the illness; making metaphors was seen as an easier task to convey specific facts using non-medical language, preferably a language that makes sense on a deeper level. Indigenous researchers in other domains have documented the use of metaphors as a familiar sense-making mechanism that allows everyone in the community to contribute to teaching and learning.23 In addition, battle and journey reflect and reinforce how an illness is experienced.24\n\nThe essence of a metaphor is to understand and experience one kind of thing in terms of another.25 Metaphors, therefore, are used cross-culturally as a tool that reflects on illness experience and may help people to express their perspectives of self physically, emotionally, spiritually, and environmentally.26 The metaphors of journey are better to use as they give a sense of purpose and control for the patient.27 It was also evident that women take this journey throughout their reproductive age and the journey only ends with pregnancy, menopause or if treated successfully.\n\nThe metaphor of the journey was also used to describe the process that women experience from being diagnosed with dysmenorrhea until being cured. The journey in this regard meant that as women go through experiencing dysmenorrhea, it is also a process from being ill to becoming healthy. The journey metaphor was found to be the language frequently used by patients, family and health caregivers.24,27,28 The metaphor of a journey, therefore, emerged as an apt description of this process, because that was how the participants spoke about their knowledge of dysmenorrhea. A journey was used to remind the women that there is a destination at the end of the travelling, although at times the road is not easy.\n\nA photograph of a chain (Figure 2) and a bridge (Figure 3) provoked a critical discussion on how women’s health issues should be approached. The participants understood dysmenorrhea as a way of indicating that the whole female reproductive system is negatively affected by illness. Dysmenorrhea was interpreted to be a holistic condition that affects women other reproductive organs rather than a specific gynecological condition.29 This means that the Batlokwa THPs and IKHs understand the science of the human body - that it is divided into systems and can identify the women’s reproductive organs.30\n\nThe participants used bridge and messenger to argue on grouping women’s gynecological issues in understanding dysmenorrhea holistically. The term bridge emerged from a photograph of a bridge (Figure 3) presented by some participants as one way of understanding the findings linking dysmenorrhea to other women’s health issues. The discussion revealed that the use of a bridge was applied as a throughway to identify other women’s health issues causing dysmenorrhea because the pain from dysmenorrhea was associated to other hidden illnesses that women might be suffering from such as infertility. The metaphor of the bridge closes a gap between the patient’s experiences of illness and the way the health care practitioners perceive it.31 When connecting dysmenorrhea to other gynecological issues, some THPs and IKHs indicated that they suffered from dysmenorrhea themselves. This resulted with infertility which was treated indigenously and in turn corrected dysmenorrhea. This finding suggests that dysmenorrhea is related to some form of infertility in women and act as a messenger agent. The findings are aligned to the study that revealed dysmenorrhea caused by endometriosis as the most leading symptom that contributes to infertility.32 The number of studies confirmed that dysmenorrhea might be a sign of infertility owing to the link between dysmenorrhea and endometriosis, which confirmed to be a cause of infertility.29,33,34 Furthermore, the authors indicated that penetrating menstrual cramps can be caused by several diseases that impact fertility. Moreover, all the participating women associated dysmenorrhea with infertility.\n\nAdditionally, the findings showed that the Batlokwa women believed that dysmenorrhea is a message indicating problems within the reproductive system of a woman. A metaphor of messenger create links between activities and behaviors to assist women to understand the signs and symptoms of dysmenorrhea that they experienced.35 Therefore, messages of health have tremendous power to effect changes in the behaviors.36 This provided evidence that messages can increase the effectiveness in the understanding and promoting health.\n\n\nLimitation of the study\n\nDespite the careful selection of the research design, this study was contextualised to a specific setting, in one village of the entire Molemole municipality, which potentially limits the generalization of findings to the entire population but only of the selected municipality. The photovoice methodology made it difficult to know if data saturation was reached or not. The researchers relied on the consensus reached during Lekgotla discussion.\n\n\nConclusion\n\nIn summary, this study engaged the Batlokwa THPs and IKHs to understand indigenous perspectives of dysmenorrhea meaning. The findings revealed that dysmenorrhea is a holistic illness that affects the woman’s entire reproductive system. This finding has the potential to direct a more holistic focus of illnesses that incorporates attention to physical and spiritual, as well as emotional and mental aspects. Therefore, the holistic understanding of dysmenorrhea teaches us that we cannot compartmentalize or separate illnesses affecting women’s reproductive system. This study provided indigenous knowledge in health that can be used in future research.\n\n\nData availability\n\nThe datasets are currently not publicly available due to data protection issues since participants data cannot be effectively de-identified. Readers may request access from the corresponding author (Melitah.Rasweswe@up.ac.za). Access will be granted for review purposes.\n\nZenodo: The indigenous meaning of dysmenorrhea: using modified photovoice to document perspectives of traditional health practitioners (THPs) and indigenous knowledge holders (IKHs). http://doi.org/10.5281/zenodo.5111345.37\n\nThe project contains the following extended data:\n\n• F1000_consent_form.doc\n\n• F1000_guidelines_for_photovoice_and_interview_guide.doc\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 all the Batlokwa THPs and IKHs for contributing in this study.\n\n\nReferences\n\nBernardi M, Lazzeri L, Perelli F, et al.: Dysmenorrhoea and related disorders. F1000Res. 2017 Sep 5; 6, 1645. eCollection 2017. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDe Sanctis V, Soliman AT, Elsedfy H, et al.: Dysmenorrhea in adolescents and young adults: a review in different countries. Acta Biomed. 2016; 87(3): 233–246. PubMed Abstract\n\nOni HT, Tshitangano TG: Prevalence of menstrual disorders and its academic impact. Kamla-raj, j hum ecol. 2015; 51(1 and 2): 214–219.\n\nBoot GR, Lowell A: Acknowledging and Promoting Indigenous Knowledges, Paradigms, and Practices Within Health Literacy-Related Policy and Practice Documents Across Australia, Canada, and New Zealand. Int Indigenous Policy J. 2019; 10(3). Publisher Full Text Reference Source\n\nRankoana SA, Nel K, Mothibi K, et al.: The use of indigenous knowledge in primary health care: A case study of Makanye community in Limpopo Province, South Africa. African J Physical, Health Education, Recreation and Dance, Supplement . 2015; 1(2): 272–278.\n\nNemutandani SM, Hendricks SJ, Mulaudzi MF: Perceptions and experiences of allopathic health practitioners on collaboration with traditional health practitioners in post-apartheid South Africa. Afr J Prm Health Care Fam Med . 2016; 8(2).PubMed Abstract | Publisher Full Text | Free Full Text\n\nSouth African National Department of Health: Efforts to Strengthen and Promote Traditional Medicine. Pretoria. Department of Health . 2015. Reference Source\n\nDe Wet H, Ngubane SC: Traditional herbal remedies used by women in a rural community in northern Maputaland (South Africa) for the treatment of gynecology and obstetrics complaints. South African J Botany. 2014: 129–139. Publisher Full Text\n\nWong CL, IP WY, Lam LW: Self-care strategies among Chinese adolescent girls with dysmenorrhea: A qualitative study. Pain Manag Nurs. 2016; 17(4): 262–271. PubMed Abstract | Publisher Full Text\n\nBehmanesh E, Delavar MA, Kamalinejad M, et al.: Effect of eryngo (Eryngium caucasicum Trautv) on primary dysmenorrhea: A randomized, double-blind, placebo-controlled study. Taiwan J Obstet Gynecol. 2019; 58: 227–233. PubMed Abstract | Publisher Full Text\n\nLi J-L: Cultural barriers lead to inequitable healthcare access for aboriginal Australians and Torres Strait Islanders. Chinese Nurs Res. 2017; 4(4): 207–210. Publisher Full Text\n\nPetre G: The School of My Dreams: Perceiving the Unspoken Desires of Undergraduate Students Through Photovoice. Int Forum. 2019; 22(1).\n\nLatz AO: Photovoice research in education and beyond: A practical guide from theory to exhibition . New York: Routledge; 2017.\n\nWang C, Burris MA: Photovoice: Concept, methodology, and use for participatory needs assessment. Health Educ Behav. 1997; 24: 369–387. PubMed Abstract | Publisher Full Text\n\nHussey W: Slivers of the journey: The use of Photovoice and storytelling to examine female to male transsexuals' experience of health care access. J Homosex. 2006; 57(1): 129–158. PubMed Abstract | Publisher Full Text\n\nMphuti DD: Anti-viral properties of wildeals (Artemisia afra) and wynruit (Ruta graveolens) as combination therapy and its effects on the renal system. PhD thesis. North-West University: South Africa; 2015.\n\nHernandez M, Gibb JK: Culture, behavior and health. Evolution, Medicine, and Public Health. 2020: 12–13. Publisher Full Text\n\nRose G: Visual Methodologies: An introduction to researching with visual methods . 3rd ed. Thousand Oaks, CA: SAGE Publications, Inc.; 2012.\n\nMji G: Exploring the health knowledge carried by older Xhosa women in their home situation, with special focus on indigenous knowledge. SUNScholar Research Repository. PhD Thesis. South Africa: Stellenbosch University; 2013.\n\nMothibe ME, Sibanda M: African traditional medicine: South African perspective. Traditional and Complementary Medicine . 2019. Publisher Full Text\n\nMathibela MK, Egan BA, Du Plessis HJ, et al.: Socio-cultural profile of Bapedi traditional healers as indigenous knowledge custodians and conservation partners in the Blouberg area, Limpopo Province, South Africa. J Ethnobiol Ethnomed. 2015; 11: 49. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization and the United Nations Children’s Fund (UNICEF): Primary health care: closing the gap between public health and primary care through integration. Technical series on primary health care. Geneva: UN; 2018.\n\nFredericks B, Clapham K, Bessarab D, et al.: Developing Pictorial Conceptual Metaphors as a means of understanding and changing the Australian Health System for Indigenous People. Action Learning Action Res J. 2015; 21: 77–107.\n\nSemino E, Demjén Z, Demmen J, et al.: The online use of ‘Violence’ and ‘Journey’ metaphors by cancer patients, as compared with health professionals: A mixed methods study. BMJ Support Palliat Care. 2017; 7(1): 60–66. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaylor C, Dewsbury BM: On the Problem and Promise of Metaphor Use in Science and Science Communication. J Microbiol Biol Educ. 2018; 19(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nLandau MJ: Using Metaphor to Find Meaning in Life. Am Psychol Assoc. 2018; 22(1): 62–72. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSemino E, Demjén Z, Hardie A, et al.: Metaphor, cancer and the end of life: A corpus-based study . London, UK: Routledge; 2018.\n\nDemmen J, Semino E, Demjén Z, et al.: A computer-assisted study of the use of violence metaphors for cancer and end of life by patients, family carers and health professionals. Int J Corpus Linguistics. 2015; 22(2): 205–231. Publisher Full Text\n\nConney CS, Kretchy IA, Asiedu-Danso M, et al.: Complementary and Alternative Medicine Use for Primary Dysmenorrhea among Senior High School Students in the Western Region of Ghana. Obstet Gynecol Int. 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStallbaum JH, da Silva FS, Saccol MF, et al.: Postural control of women with primary dysmenorrhea in different phases of the menstrual cycle. Fisioter Pesqui. 2018; 25(1): 74–81. Publisher Full Text\n\nPenson RT, Schapira L, Daniels KJ, et al.: Cancer as metaphor. Oncologist. 2004; 9(6): 708–716. PubMed Abstract | Publisher Full Text\n\nGad M, Abdel-Gayed AMA, Dawoud RM, et al.: Prevalence of endometriosis in unexplained infertility and chronic pelvic pain in women attending Menoufia University Hospital. Menoufia Med J. 2017; 30(2): 356–360. Publisher Full Text\n\nAjayi AB, Ajayi VD, Biobaku O, et al.: A 10-year study of endometriosis in an indigenous Black African population. J Endometriosis Pelvic Pain Disorders. 2016; 8(4): 157–166. Publisher Full Text\n\nCochrane S, Smith CA, Possamai-Inesedy A: Development of a fertility acupuncture protocol: defining an acupuncture treatment protocol to support and treat women experiencing conception delays. J Altern Complement Med. 2011; 17(4): 329–337. PubMed Abstract | Publisher Full Text\n\nArmour M, Dahlen H: A change of perspective: treatment for period pain using acupuncture alters how women view their menstrual cycle. Integrative Med Res. 2015. Publisher Full Text\n\nLazard AJ, Bamgbade BA, Sontag JM, et al.: Using Visual Metaphors in Health Messages: A Strategy to Increase Effectiveness for Mental Illness Communication. J Health Commun. 2016; 21(12): 1260–1268. PubMed Abstract | Publisher Full Text\n\nRasweswe MM, Peu MD, Mulaudzi FM: The indigenous meaning of dysmenorrhea: using modified photovoice to document perspectives of traditional health practitioners (THPs) and indigenous knowledge holders (IKHs). Zenodo. 2021, July 17. Publisher Full Text"
}
|
[
{
"id": "97952",
"date": "26 Oct 2021",
"name": "Firoza Haffejee",
"expertise": [
"Reviewer Expertise Public Health",
"HIV"
],
"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 general, the paper is written well and suitable for research using the photovoice technique. The grammar however, requires improvement. Please also address the following queries:\nIntroduction line 4, “literature view” should be “literature review”.\n\nReference required for sample size of 7-10 being adequate.\n\nIt is not clear whether the interviews were conducted in English, the local indigenous language or both. Please clarify. Also, indicate what measures were taken to ensure that translations were correct and captured the essence of what the participant was saying (if a language other than English was used).\n\nIn the results section – just before Figure 1 – in the quote of participant 2, “being” should be ‘been’.\n\nLast paragraph under the section process or journey….. – “on the other side’ should be ‘on the other hand’. Similarly, change “on the other vein” in the next paragraph.\n\nIn the discussion it is stated that the picture of the bridge evoked “critical discussion” but that is not given in the results. Please expand.\"\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": []
}
] | 1
|
https://f1000research.com/articles/10-672
|
https://f1000research.com/articles/10-398/v1
|
18 May 21
|
{
"type": "Brief Report",
"title": "Isolation of active Averrhoa bilimbi phytocompounds corresponding to brown adipocytes stimulation",
"authors": [
"Mohamad Faiz Hamzah",
"Azimah Amanah",
"Wai Kwan Lau",
"Mohamad Faiz Hamzah",
"Azimah Amanah"
],
"abstract": "Averrhoa bilimbi is a fast-growing tree widely found in countries of tropical Asia. Due to easy accessibility and traditional knowledge, various parts of this plant are adopted as folk medicine and a natural health remedy. Recently, beneficial effects of bilimbi in combating obesity including its potential antihyperlipidemic and hypoglycemic activities have been discovered. This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. Bilimbi ethanolic extract underwent bioassay-guided partitioning and fractionation. The n-hexane partition exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further isolation of this active partition yielded 10 fractions. Active fractions with the highest brown adipogenesis potential were further evaluated via the adipomyocytes assay. Chemical structures of the constituents were elucidated by gas chromatography-mass spectrometry (GC-MS). Major phytocomponents in the n-hexane partition include hexadecanoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene.",
"keywords": [
"Averrhoa bilimbi",
"obesity",
"brown adipocytes",
"white adipocytes",
"adipomyocytes"
],
"content": "1. Introduction\n\nAverrhoa bilimbi, also known as bilimbi by locals, is widely found in many countries of tropical Asia including Malaysia, the Philippines, Indonesia, and India. Bilimbi is a fast growing and long-lived plant species that is commonly 16-33 feet tall.1 It belongs to the same Oxadilaceae family as the carambola or star fruit. Scientific studies have been conducted on various parts of this plant, with medicinal benefits including antioxidant, hepatoprotective, anti-cancer, wound healing, anti-diabetic, anti-hyperlipidemic, anti-hypertensive, anti-hypercholesterolemic, anti-ulcerative colitis effects, as well as attenuated hyperglycermia-mediated oxidative stress and anti-thrombotic activities.2–5 Its beneficial effects in brown adipogenesis activation, a phenomenon that combats obesity, has also been recently reported.6\n\nThere are two main types of adipose tissue. White adipose tissue (WAT) is the primary site of fat storage and its amount increases in obesity. Brown adipose tissue (BAT) on the other hand plays specific roles in promoting energy expenditure and maintaining body temperature via heat generation. Although BAT and WAT are originated from distinct lineages, the plasticity of WAT allows brown adipocyte-like cells to emerge upon appropriate and adequate stimulation. This process is termed “browning” or “beiging” of WAT, which induces thermogenesis in cellular and animal models.7–9 Fundamental to the development of obesity is an imbalance between caloric intake and energy expenditure. The induced BAT development from WAT may help to increase energy consumption as well as reduce adverse effects of WAT to improve metabolic health. The stimulation of BAT development and activity can also be strategised to combat obesity.\n\nAlthough the molecular effects of bilimbi in stimulating BAT activity to combat diet-induced obesity has been investigated recently, the corresponding phytocompounds to the reported pharmacological effects remain poorly studied. Here, we identify the phytocompounds of plant partition, and its active fractions that induce BAT associated adipomyocytes differentiation and enhance brown adipogenesis activities.\n\n\n2. Methods\n\nBilimbi leaves were sampled from an orchard with the owner’s permission. The botanical authentication of the specimen was conducted by botanists of the School of Biological Sciences, Universiti Sains Malaysia (USM) and a voucher specimen 11738 was deposited in the herbarium of USM. Fresh leaves were dried in an oven at 45°C until the percentage yield of moisture content value was less than 10%. Dried leaves were then ground to a fine powder using a grinder then weighed, recorded and kept in a plastic bag. The powder was soaked in ethanol (EtOH) for 3 days at room temperature. After filtration with Whatman No. 1 filter paper, the solvent was removed under reduced pressure at 40°C using a rotary evaporator (Buchi, Switzerland) to obtain the crude ethanolic extract. The weight and percentage yield were recorded, stored in an amber bottle, labelled and kept refrigerated until further use. Next, the crude was sequentially extracted with organic solvents - namely n-hexane (n-Hex), ethyl acetate (EtOAc), and n-butanol (n-BuOH) with increasing polarity respectively. The filtrate was then concentrated and dried under reduced pressure at 40°C using a Buchi rotary evaporator. The remaining ethanolic aqueous layer was evaporated and lyophilised in a freeze-dryer. The weight and percentage of each yield was recorded and kept refrigerated. A flow diagram showing the step-by-step extraction and partitioning processes is depicted in Figure 1.\n\nAfter the bioactivity of these extracts was confirmed in cell-based assays, 200g of dried leaves was soaked in 15L of n-Hex to yield 12 g of extract. Fractionation was conducted with normal phase silica gel flash column chromatography. Mobile phases in the separation consisted of gradient of n-Hex, EtOAc, and methanol.\n\nHPTLC has advanced separation efficiency and detection limits compared to conventional TLC Chromatography. The pre-coated silica gel Merck, TLC silica gel plates 60 F 254, 200 × 100 mm were used. 2 μL of the sample solution was applied on the plate using a CamagLinomat V automatic sampler applicator in the form of bands (length: 5 mm, width: 1 mm, distance between two bands: 10 mm) by using a 100 μL Camag Microlitre Syringe (Hamilton, Bonaduz, Switzerland). A constant application rate of 150 nL/s with mobile phase of n-hexane: ethyl acetate (80:20, v/v) was adopted. The plate was then placed in the mobile phase, and ascending development was performed to a distance of 8.5 cm, the plate was then air dried and performed densitometry scanning at 250 nm. Images of the TLC plates were captured using the Camag’s TLC Visualizer documentation system. The system provided illumination with white light (remission, transmission or a combination of both), where the exposure of RT white was optimised at 1.482 s, R 254 at 0.185 s, and R 366 at 0.877 s.\n\nC2C12 myoblast was purchased from the American Type Culture Collection (Manassas, VA, USA) and was maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Rosiglitazone, a PPARgamma agonist with known browning activities on both classic white adipocytes and inducible brown adipocytes, was used as the positive control.10,11 Adipocyte differentiation in the myoblast was initiated after the cells reached confluent by adding 0.5mM isobutyl methylxanthine (IBMX), 1μM dexamethasone (DEX), 1μg/ml insulin, and 1μM rosiglitazone (ROSI). Fresh differentiation medium containing DMEM, 10% FBS, 1μg/ml insulin and 1μM ROSI was replaced two days later. These cells were then stabilised in DMEM containing 10% FBS for another two days until the formation of oil droplets was observed.\n\nCells were washed once with PBS and fixed with 4% paraformaldehyde for ten minutes. Lipid droplets produced by adipocytes were stained by Nile Red solution and were visualised using the IN Cell 2200 Analyzer High Content Screening System (GE Healthcare, PA, USA) at an excitation wavelength of 460 nm.\n\nThe GC/MS analyses were carried out using the Agilent 5977A Series GC/MSD system with an HP-5ms ultra inert column (30 m × 0.25 mm id, 0.25 μm film thicknesses). Spectroscopic detection by CG/MS involved an electron ionisation system which utilised high energy electrons (70 eV). Pure helium gas (99.995%) was used as the carrier gas with a flow rate of 1 mL/min. The initial GC oven temperature was set as 110°C for two minutes and programmed with increasing rate of 10°C/min to 200°C in five minutes. Finally, the temperature was increased to 250°C at 10°C/min in five minutes and held at that temperature for 13 minutes. The split ratio was 1:25 with a scan range of 40 to 550 amu. Hexane fraction (1 μL, 1 mg/mL) and extract (3 μL, 10 mg/mL) diluted in n-Hex were injected into the GC/MS via an auto-injector. Phytochemical constituents were identified based on the comparison of their mass spectra of the MassHunter Library WION 14.L.\n\n\n3. Results\n\nFour partitioned extracts were in the yield: n-Hex, EtOAc, n-BuOH and water extracts. The yield of each component is indicated in Figure 1.\n\nFlash column chromatography was conducted on the plant extract with an equilibration solvent ratio of n-Hex and EtOAc (95:5). A Hi Flash Column with a size of 3L (46 × 130mm silica gel) was used. With a flow rate of 60 ml/min, a total of 80 fractions were collected and spotted on a plate, employing the HPTLC. Plate visualisation was done under short (254 nm) and long wavelength (366 nm) ultraviolet lights, as well as white light illumination. Fractions with similar separation profiles were pooled. A total of ten fractions were collected with respective TLC profiles as shown in Figure 2.\n\nTwo batches (1 & 2) of fractionation samples were collected and run on the same plates (A) TLC plate image viewed under UV 254 nm. (B) TLC plate image viewed under UV 366 nm. (C) TLC plate image viewed under white light illumination.\n\nThe partitioned extracts and fractions corresponded to the growth stimulation of brown adipocyte were investigated via cell-based study. The myf5-positive characteristics of C2C12 murine myoblast allow the co-development of mature myotubes and brown adipocytes upon appropriate stimulations. ROSI was served as the positive control. Adipogenesis was observed on day four after treatment with 1μM ROSI. A similar phenomenon was found in 200 μg/ml EtOH and 100 μg/ml n-Hex treated cells. Myotube development was observed in all treated cells. All positively treated cells showed intracellular lipid droplet production after 7 days of incubation. These lipid droplets were captured by Nile Red staining and imaged at 20× magnification (Figure 3). Among the four partitioned extracts tested, n-Hex exhibited the highest amount of lipid droplet production.\n\nLipid droplets formation upon adipogenesis upon treatment by (A) 200 μg/ml EtOH, (B) 1 μM ROSI, (C) 100 μg/ml n-Hex, (D) 100 μg/ml EtOAc, (E) 100 μg/ml n-BuOH and (F) H2O were stained by a Nile Red solution. Treatment of myoblasts with adipogenesis stimulants facilitated myocytes and adipocytes co-differentiation.\n\nA bioassay guided fractionation technique was used to identify the active components present, as well as to evaluate the corresponding phytocompounds in brown adipocyte activation.\n\nThe cell-based study was then repeated on ten n-Hex fractions yielded from the HPTLC fractionation. Cell morphology and lipid droplet accumulation was observed for seven days with treatments by ten fractions. Myotube development was observed in all treated cells. Adipocyte differentiation was also observed in f5, f6, f8, f9 and f10 treated cells, with lipid droplet formation as depicted in Figure 4. Massive death was observed in f7 treated cells on day 3, and cell death was also found in f6 treatment from day 5 onwards. DMSO was used to replace bilimbi and ROSI in non-treated cells. These negative control cells were supplemented with adipogenesis culturing media and were fully developed into myotubes.\n\nLipid droplet formation upon treatment by n-Hex fractions (f1 – f10) and 1 μM ROSI were stained by a Nile Red solution. n-Hex fractions with adipogenesis stimulating components facilitated myocyte and adipocyte co-differentiation. Cells treated with 0.5% DMSO served as negative control (-ve) and demonstrated a complete process of myogenesis.\n\nA GC/MS based qualitative analysis was performed on n-Hex and subsequently three active fractions, namely f8, f9, and f10, to determine the types of compounds present (Figure 5-8). Major constituents identified are presented in Tables 1 & 2. Studies on f6 & f7 were discontinued after the demonstration of cytotoxic effect in these treated cells, as shown in Figure 4.\n\nThe database information search via the MassHunter Library WION 14.L revealed the presence of nine predominant compounds in f8, ten in f9, and five in f10. (1.alpha., 4.alpha., 4a.alpha., 10a.alpha.) -1, 4, 4a, 5, 6, 7, 8, 9, 10, 10a -decahydro- 1, 4, 11, 11-tetramethyl-1, 4-methanocycloocta [d] pyridazine and i-propyl 3- (phenylamino) -2- (phenylseleno) -3- (phenyl) propanoate were detected in all the three fractions whereas nonanal and hexadecanoic acid were commonly present in f9 and f10. The high abundance compounds include 3-nonen-2-one; 2(4H)-Benzofuranone, 5, 6, 7, 7a-tetrahydro -6- hydroxy-4, 4, 7a-trimethyl-, (6S-trans)-; hexadecanoic acid; (12R)-(9Z)-12-hydroxy-9-octadecenoic acid; spiro [2.4] heptanes-5-carboxaldehyde; and i-propyl 3 -(phenylamino) -2- (phenylseleno) -3- (phenyl) propanoate.\n\n\n4. Discussion\n\nBrown adipocytes and myocytes, precursor cells that give rise to skeletal muscle, are developed from a common adipomyocyte precursor. White adipocytes on the other hand are derived from pericytes that embedded within the vascular vessel walls. In this study, a straightforward cell-based assay was adopted based on the unique characteristics of precursor cells, where the adipomyocytes containing a mixture of brown adipocytes and myocytes, or solely the myocyte differentiation program, was activated via its initiation factors. Gene program commitments in myoblast-brown adipocyte transition were observed in bilimbi treated cells and the up-regulation of PGC-1α, UCP1 and PRDM16 proteins which influenced the cellular metabolism and mitochondrial function.6\n\nOur observations in this study showed that bilimbi n-Hex partition was able to induce a higher cellular response in signalling the co-development of brown adipocytes and myocytes than its crude extract. The induction of brown adipocyte differentiation indicates the presence of active phytocomponents that are responsible for the program. Major phytocomponents in the n-Hex partition include hexadecenoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene, which agree with an earlier report.12 Bioassay-guided fractionations yielded some promising bilimbi fractions from the n-Hex partition which further enhanced the brown adipogenesis program. Major chemical compounds of these fractions were then isolated and are summarised in Table 2. Some of these compounds are highly related to the obesity research in the past few years. For instance, Terbutaline is a β2-adrenergic receptor agonist that has been recognised to increase lipolysis and thermogenesis.13 2(4H)-Benzofuranone,5,6,7,7a-tetrahydro-6-hydroxy-4,4,7a-trimethyl-,(6S-trans)- is a compound that has been found to ameliorate hyperglycaemia, dyslipidaemia, and obesity in high-fat diet-fed mice.14 (12R)-(9Z)-12-hydroxy-9-octadecenoic acid, also known as ricinoleic acid, is an unsaturated omega-9 fatty acid and hydroxyl acid. Ricinoleic acid is linked to the activation of EP3 prostanoid receptor for prostaglandin E2 regulations in adipogenesis and lipolysis of WAT.15,16 i-Propyl3-(phenylamino)-2-(phenylseleno)-3-(phenyl) propanoate, detected in all the three bioactive fractions, is a short-chain fatty acid which regulates gut hormone release, suppresses food intake, and protects against diet-induced obesity.17 Hexadecanoic acid, also known as palmitic acid, is a controversial component in obesity research, where over-accumulation may result in dyslipidaemia and other obesity associated diseases.18\n\nEvolutionary processes in natural products enhance their structural diversity and shape the pathways of secondary metabolite production. Many of these metabolites play important roles as the starting points for drug discovery in both traditional and modern medicines. Besides, plants are used in the form of spices and herbs based on their natural antioxidant values. Several plant-derived nutraceuticals are found to regulate BAT activity and induced WAT metabolis, including capsenoid, curcumin, quercetin, and resveratrol, without major adverse events.19 Food ingredients that could increase BAT activity include chili peppers, turmeric, thyme, cinnamon, garlic, onion, green tea, mulberry, and cocoa. Their white-to-brown adipose tissue conversion and calorie burning properties are identified through in vitro and in vivo models.20,21 Nevertheless, the involvement of bilimbi fractions and their bioactive compounds in BAT program enhancement are reported for the first time in this study.\n\nIt is estimated that 40-50g of active BAT can increase daily energy expenditure in humans by 20%.22 This could be implemented either by enhancing the activity of BAT or by increasing the number of WAT browning. Dietary components have been shown to increase thermogenic capacity by augmenting BAT activity via several mechanisms of action. Capsaicin that is commonly found in red peppers has been shown to activate ADRB3, a member of the G protein-coupled receptor family, that induces adenyl cyclase after activation, triggering a cascade of responses in the brown adipogenic program. Resveratrol extracted from grapes and berries on the other hand activates SIRT1 to recruit the BAT program via a series of PRDM16 pathway modulators including PPARγ, C/EBPβ, PGC-1α, and UCP1.23 Bilimbi, in our studies, acted similarly by up-regulating the expression of relevant proteins which influenced the cellular metabolism and mitochondrial function in adipocyte browning. Therefore, the molecular mechanism of action behind each active compound of bilimbi should be further studied to constitute a therapeutic option for obesity treatment in the future.\n\n\n5. Conclusions\n\nIn summary, n-Hex extract of bilimbi activated the adipocyte program of adipomyocytes. Several bilimbi fractions showed strong activity in brown adipocyte differentiation from adipomyocytes. Fatty acids that were found in the n-Hex extract and fractions are potential BAT thermogenic agents. Other major phytocompounds including phytol, squalene, and terbutaline, are believed to enhance lipolysis and themogenesis of adipocyte tissues.\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\nAuthor contributions\n\nF.H., A. A. and W.K.L. conceived and designed the experiments, collected and analysed the data; the manuscript was written by W.K.L. and reviewed by F.H. & A.A.",
"appendix": "References\n\nKumari S: Studies on Bilimbi. 2017. Publisher Full Text\n\nAlhassan AM, Ahmed QU: Averrhoa bilimbi Linn.: A review of its ethnomedicinal uses, phytochemistry, and pharmacology. J Pharm Bioallied Sci. 2016; 8: 265–271. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSuluvoy JK, Sakthivel KM, Guruvayoorappan C, et al.: Protective effect of Averrhoa bilimbi L. fruit extract on ulcerative colitis in wistar rats via regulation of inflammatory mediators and cytokines. Biomed Pharmacother. 2017; 91: 1113–1121. PubMed Abstract | Publisher Full Text\n\nKurup SB, Mini S: Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. J Food Drug Anal. 2017; 25: 360–368. PubMed Abstract | Publisher Full Text\n\nPushparaj P, Tan CH, Tan BK: Effects of Averrhoa bilimbi leaf extract on blood glucose and lipids in streptozotocin-diabetic rats. J Ethnopharmacol. 2000; 72: 69–76. PubMed Abstract | Publisher Full Text\n\nLau WK, et al.: Novel discovery of Averrhoa bilimbi ethanolic leaf extract in the stimulation of brown fat differentiation program in combating diet-induced obesity. BMC Complement. Altern. Med. 2019; 19: 243. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu J, et al.: Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 150: 366–376. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharma A, et al.: Brown fat determination and development from muscle precursor cells by novel action of bone morphogenetic protein 6. PLoS One. 2014; 9: e92608–e92608. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarms M, Seale P: Brown and beige fat: development, function and therapeutic potential. Nat. Med. 2013; 19: 1252–1263. PubMed Abstract | Publisher Full Text\n\nNie B, et al.: Brown Adipogenic Reprogramming Induced by a Small Molecule. Cell Rep. 2017; 18: 624–635. PubMed Abstract | Publisher Full Text\n\nFayyad A, et al.: Rosiglitazone Enhances Browning Adipocytes in Association with MAPK and PI3-K Pathways During the Differentiation of Telomerase-Transformed Mesenchymal Stromal Cells into Adipocytes. Int. J. Mol. Sci. 2019; 20: 1618. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGunawan CA, Paano A: Structure elucidation of two new phytol derivatives, a new phenolic compound and other metabolites of Averrhoa bilimbi. in: DLSU Res. Congress 2013; 1–8.\n\nCero C, Lea HJ, Zhu KY, et al.: 2020-P: ß3-Adrenergic Receptors Regulate Lipolysis and Thermogenesis in Human Brown/Beige Adipocytes. Diabetes. 2020; 69. Publisher Full Text\n\nSirichaiwetchakoon K, Lowe GM, Kupittayanant S, et al.: Pluchea indica (L.) Less. Tea Ameliorates Hyperglycemia, Dyslipidemia, and Obesity in High Fat Diet-Fed Mice. Evid. Based. Complement. Alternat. Med. 2020; 8746137: 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTunaru S, Althoff TF, Nüsing RM, et al.: Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors. Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 9179–9184. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu H, et al.: Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue. J. Mol. Cell Biol. 2016; 8: 518–529. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLin HV, et al.: Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012; 7: e35240–e35240. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCarta G, Murru E, Banni S, et al.: Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front. Physiol. 2017; 8(902). PubMed Abstract | Publisher Full Text | Free Full Text\n\nAzhar Y, Parmar A, Miller CN, et al.: Phytochemicals as novel agents for the induction of browning in white adipose tissue. Nutr. Metab. (Lond). 2016; 13: 89. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang X, et al.: Flavonoids as inducers of white adipose tissue browning and thermogenesis: signalling pathways and molecular triggers. Nutr. Metab. (Lond). 2019; 16: 47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaito M, Matsushita M, Yoneshiro T, et al.: Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men. Front Endocrinol. 2020; 11(222). PubMed Abstract | Publisher Full Text | Free Full Text\n\nRothwell NJ, Stock MJ: Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin. Sci. (Lond). 1983; 64: 19–23. PubMed Abstract | Publisher Full Text\n\nKuryłowicz A, Puzianowska-Kuźnicka M: Induction of Adipose Tissue Browning as a Strategy to Combat Obesity. Int. J. Mol. Sci. 2020; 21. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "85583",
"date": "01 Jun 2021",
"name": "Yusuf Andriana",
"expertise": [
"Reviewer Expertise natural product chemistry"
],
"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\nHamzah et al. studied the isolation of active Averrhoa bilimbi phytocompounds corresponding to brown adipocytes stimulation. Before indexing, several points need to be clarified:\nAbstract:\nThe authors stated “This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation”.\n\nI think the authors couldn’t say “isolation and purification” because in their study, they only yielded fraction (mixture of compounds) not pure compound. I suggest to use the term “fractionation”.\n\n“…….bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation” - in this case the authors did not know exactly which compounds were responsible/linked to brown adipocyte activation. The authors just checked the mixture compounds (in F8,F9,F10), the major compounds in F8-10 didn’t correspond with brown adipocyte activation, except the authors check single compounds in F8-10.\n\nIntroduction:\nPlease add information about bioactive compounds that have been reported from Averrhoa bilimbi.\n\nMethods:\nFor Cell culture and adipocyte differentiation, Adipocyte determination by fluorescent dye staining, GC/MS analyses and identification of components were needed to add citations, from where did the authors obtain the method, did the authors develop the methods by themselves?\n\nFor GC-MS, the authors should explain why they use the HP5-MS column as the column was a non-polar column, it is better to use more general columns such as DB5-MS, because in Figure 3, ethanol extract seems to show lipid droplet formation upon similar with the standard (ROSI) and hexane extract. I mean maybe the polar compounds might be also responsible for this activity.\n\nResults:\nIn GC-MS result, it is better to present Retention Index, so please change retention time to retention index following NAST.\n\nIn hexane extract, Phytol (14.82%), 9-Octadecanoic acid-Z- (19.69%), and Squalene (100.00%) (Table 1) - How can % area be more than 100%?\n\nIt seems phytol, 9-Octadecanoic acid-Z-, Squalene were the major compounds, but why in the F8,9,10 they weren't detected?\n\nI think you should conduct GC-MS analysis at least twice and present as mean ± standard deviation, to make your research more producible.\n\nConclusion:\nDid you detect, squalene, and terbutaline in F8,9,10? There is no strong evidence to say that these compounds enhance lipolysis and thermogenesis of adipocyte tissues.\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? Yes\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": "7395",
"date": "08 Dec 2021",
"name": "Wai Kwan Lau",
"role": "Author Response",
"response": "Reviewer 1 Hamzah et al. studied the isolation of active Averrhoa bilimbi phytocompounds corresponding to brown adipocytes stimulation. Before indexing, several points need to be clarified: Abstract: The authors stated “This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation”. I think the authors couldn’t say “isolation and purification” because in their study, they only yielded fraction (mixture of compounds) not pure compound. I suggest to use the term “fractionation”. “…….bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation” - in this case the authors did not know exactly which compounds were responsible/linked to brown adipocyte activation. The authors just checked the mixture compounds (in F8,F9,F10), the major compounds in F8-10 didn’t correspond with brown adipocyte activation, except the authors check single compounds in F8-10. Response to reviewer: The Title and Abstract sections have been reworded to extraction and fractionation accordingly. The Abstract has also been rewritten to better reflect the current findings of this study. Introduction: Please add information about bioactive compounds that have been reported from Averrhoa bilimbi. Response to reviewer: This was included in the second paragraph of Discussion section where two references were cited (Gunawan et al, 2013; Saini, 2016). “Major phytocomponents in the n-Hex partition include hexadecenoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene, which agree with earlier reports.” Methods: For Cell culture and adipocyte differentiation, Adipocyte determination by fluorescent dye staining, GC/MS analyses and identification of components were needed to add citations, from where did the authors obtain the method, did the authors develop the methods by themselves? For GC-MS, the authors should explain why they use the HP5-MS column as the column was a non-polar column, it is better to use more general columns such as DB5-MS, because in Figure 3, ethanol extract seems to show lipid droplet formation upon similar with the standard (ROSI) and hexane extract. I mean maybe the polar compounds might be also responsible for this activity. Response to reviewer: References for cell culture, adipocyte differentiation and adipocyte determination methods (Sharma et al, 2014; Melhem et al 2013) have been included. References for GC/MS method and analysis (Azeem, 2015; Suluvoy et al, 2017) have also been cited. The GC/MS detection focused on hexane extract and fractions which in this study showed best biological activity for brown adipocyte activation. The non-polar column was used because hexane is a non-polar solvent which extract non-polar extracts and compounds. Please refer to Section 2.5 for further elaboration of the method. Results: In GC-MS result, it is better to present Retention Index, so please change retention time to retention index following NAST. In hexane extract, Phytol (14.82%), 9-Octadecanoic acid-Z- (19.69%), and Squalene (100.00%) (Table 1) - How can % area be more than 100%? It seems phytol, 9-Octadecanoic acid-Z-, Squalene were the major compounds, but why in the F8,9,10 they weren't detected? I think you should conduct GC-MS analysis at least twice and present as mean ± standard deviation, to make your research more producible. Response to reviewer: The GC/MS results which were reported based on the database NIST-WILEY have been re-tabulated in Table 1. Standard compounds of squalene and phytol isomers are purchased for this purpose. The standard compounds are spotted with the hexane partition extract and fractions on a TLC plate as shown in the figure below to confirm the GC/MS analysis. It is indicated that squalene and phytol compounds do not or minutely present in F8-F10 and therefore were not being detected in the GC/MS. Hex F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Phy Sq Hex: n-Hex extract F1 – F10: Fractions Phy – Standard Phytol Isomers Sq – Standard Squalene Conclusion: Did you detect, squalene, and terbutaline in F8,9,10? There is no strong evidence to say that these compounds enhance lipolysis and thermogenesis of adipocyte tissues. Response to reviewer: These compounds have been removed from the Conclusion section and only their potential functions are being discussed in the Discussion section."
}
]
},
{
"id": "87939",
"date": "08 Jul 2021",
"name": "Nor Akmalazura Jani",
"expertise": [
"Reviewer Expertise Natural product chemistry"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nTitle The word “isolation” is incorrect since the authors does not obtain any pure compounds from Averrhoa bilimbi. Therefore, the authors should revise the title of manuscript.\nAbstract \"This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. Bilimbi ethanolic extract underwent bioassay-guided partitioning and fractionation. The n-hexane partition exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further isolation of this active partition yielded 10 fractions. Active fractions with the highest brown adipogenesis potential were further evaluated via the adipomyocytes assay.\"\n\nThe authors performed the bioassay-guided fraction approach to afford the active fraction corresponds to brown adipocyte activation. Thus, the terms “isolation and purification” are incorrect. I think the word “fractionation” is more suitable.\n\"Chemical structures of the constituents were elucidated by gas chromatography-mass spectrometry (GC-MS).\"\n\nGC-MS is used to identify the presence of compounds within a test sample. Basically, the chemical structures of organic compounds are elucidated by spectroscopic techniques including NMR, IR, MS and UV. I think the authors should revise the above-mentioned sentence.\nThe authors can include the active fractions as well as compounds detected by GC/MS from the active fractions. I think the compounds identified from the n-hexane partition are not that necessary to be included in the abstract.\nIntroduction Please include literature review on the phytochemicals of Averrhoa bilimbi.\nMethods 2.1 Plant extractions and fractions with Flash Column Chromatography\nFigure 1: Please rearrange yield of F1 until F10.\nResults Please change title for section 3.1 to \"Biological Assay-Guided Fractionation of A. bilimbi Extract\".\n3.2 Flash Column Chromatography and High-Performance Thin Layer Chromatography (HPTLC)\nThe TLC plates were visualized under UV (254 and 366 nm) and white light illumination. However, based on Tables 1 and 2, most of the detected compounds are weakly- or not chromophore in which their spot maybe could not detected by the UV light and/or white light illumination. I think the authors can use a TLC visualization reagent such as vanillin sulfuric acid reagent to detect weakly- and non-chromophore compounds to see the whole TLC profile of the extracts and fractions. Reference: https://link.springer.com/content/pdf/bbm%3A978-3-662-02398-3%2F1.pdf.\n3.4 Gas-Chromatography/Mass-Spectrometry (GC/MS)\nPlease revise the title of Figures 5-8. The title should be GC chromatogram of (tested sample) not mass spectrum of (tested sample). A mass spectrum is an intensity versus m/z (mass-to-charge ratio) plot representing a chemical analysis, while GC chromatogram is a plot of an intensity/abundance versus retention time.\n\nPlease revise the percent area of each compound in the n-hexane partition. The total percent should not exceed 100%.\n\nPlease use subscript to write number of atoms in the molecular formula. For example, H2O.\n\nWhy does the m/z of the detected compound not match with the exact molecular weight of the compound?\n\nWhy were the major compounds in the n-hexane partition (i.e., hexadecanoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene) not detected in any active fractions?\n\nExplain why the majority of compounds in the n-hexane partition and active fractions were not similar.\nDiscussion Second paragraph: Major chemical compounds of these fractions were then isolated and are summarised in Table 2.\nPlease revise the term “isolated”. I think the sentence should be “The major chemical compounds in the active fractions were listed in Table 2”.\nConclusions I think the authors should revise the statement related to the detected compounds in the n-hexane partition and active fractions. I recommended to add further study such as isolation of compound from the active fractions.\nTechnical n-hexane and n-butanol: the alphabet “n” should be written in italic (n-hexane, n-butanol, n-Hex, n-BuOH).\nPlease give a space between number and unit. For example, 20 g instead of 20g.\nPlease add a comma before the word \"whereas\". For example: \"_______, whereas\".\nThe term “GC-MS” should be written consistently either as “GC-MS” or “GC/MS”.\nThe abbreviation of litre should be written as “L” in capital letter.\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? Partly\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": "7396",
"date": "08 Dec 2021",
"name": "Wai Kwan Lau",
"role": "Author Response",
"response": "Reviewer 2 Title The word “isolation” is incorrect since the authors does not obtain any pure compounds from Averrhoa bilimbi. Therefore, the authors should revise the title of manuscript. Response to reviewer: The Title section has been rephrased to “fractionation”. Abstract \"This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. Bilimbi ethanolic extract underwent bioassay-guided partitioning and fractionation. The n-hexane partition exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further isolation of this active partition yielded 10 fractions. Active fractions with the highest brown adipogenesis potential were further evaluated via the adipomyocytes assay.\" The authors performed the bioassay-guided fraction approach to afford the active fraction corresponds to brown adipocyte activation. Thus, the terms “isolation and purification” are incorrect. I think the word “fractionation” is more suitable. \"Chemical structures of the constituents were elucidated by gas chromatography-mass spectrometry (GC-MS).\" GC-MS is used to identify the presence of compounds within a test sample. Basically, the chemical structures of organic compounds are elucidated by spectroscopic techniques including NMR, IR, MS and UV. I think the authors should revise the above-mentioned sentence. The authors can include the active fractions as well as compounds detected by GC/MS from the active fractions. I think the compounds identified from the n-hexane partition are not that necessary to be included in the abstract. Response to reviewer: The Abstract section has been reworded to extraction and fractionation accordingly. The last sentence which describes compounds identified from the n-hexane partition have been removed. Introduction Please include literature review on the phytochemicals of Averrhoa bilimbi. Response to reviewer: This was included in the second paragraph of Discussion section where two references were cited (Gunawan et al, 2013; Saini, 2016). “Major phytocomponents in the n-Hex partition include hexadecenoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene, which agree with earlier reports.” Methods 2.1 Plant extractions and fractions with Flash Column Chromatography Figure 1: Please rearrange yield of F1 until F10. Response to reviewer: Figure 1 has been rearranged to align the label and yield of f1 - f10. Results Please change title for section 3.1 to \"Biological Assay-Guided Fractionation of A. bilimbi Extract\". 3.2 Flash Column Chromatography and High-Performance Thin Layer Chromatography (HPTLC) The TLC plates were visualized under UV (254 and 366 nm) and white light illumination. However, based on Tables 1 and 2, most of the detected compounds are weakly- or not chromophore in which their spot maybe could not detected by the UV light and/or white light illumination. I think the authors can use a TLC visualization reagent such as vanillin sulfuric acid reagent to detect weakly- and non-chromophore compounds to see the whole TLC profile of the extracts and fractions. Reference: https://link.springer.com/content/pdf/bbm%3A978-3-662-02398-3%2F1.pdf. 3.4 Gas-Chromatography/Mass-Spectrometry (GC/MS) Please revise the title of Figures 5-8. The title should be GC chromatogram of (tested sample) not mass spectrum of (tested sample). A mass spectrum is an intensity versus m/z (mass-to-charge ratio) plot representing a chemical analysis, while GC chromatogram is a plot of an intensity/abundance versus retention time. Please revise the percent area of each compound in the n-hexane partition. The total percent should not exceed 100%. Please use subscript to write number of atoms in the molecular formula. For example, H2O. Why does the m/z of the detected compound not match with the exact molecular weight of the compound? Why were the major compounds in the n-hexane partition (i.e., hexadecanoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene) not detected in any active fractions? Explain why the majority of compounds in the n-hexane partition and active fractions were not similar. Response to reviewer: Title for section 3.1 has been reworded accordingly. 3.2 Flash Column Chromatography and High-Performance Thin Layer Chromatography (HPTLC) A TLC plate with vanillin sulfuric acid reagent development has been provided as follows: Hex F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Phy Sq Hex: n-Hex extract F1 – F10: Fractions Phy – Standard Phytol Isomers Sq – Standard Squalene 3.4 Gas-Chromatography/Mass-Spectrometry (GC/MS) Figure 5 – 8 have been reworded accordingly. The % area of each compound has been revised and tabulated in Table 1 & 2. Revision has been made on the molecular formula according to the format as requested, as tabulated in Table 1 & 2. m/z refers to the base peak and mass DB refers to the molecular weight of compound. From the TLC plate developed under vanillin sulfuric acid reagent, these compounds did not present in F8-F10 and therefore were not being detected in GC/MS. Standard compounds of squalene and phytol isomers have been purchased to be spotted with the hexane partition extract and fractions as references.The squalene compound was only seen in F1 and F2. Some of the compounds in hexane extract are weakly or not detected compared to fractions because during fractionation the extract was fractionated and concentrated. Besides, major compounds in hexane extract in this study could be present in other fractions. Discussion Second paragraph: Major chemical compounds of these fractions were then isolated and are summarised in Table 2. Please revise the term “isolated”. I think the sentence should be “The major chemical compounds in the active fractions were listed in Table 2”. Response to reviewer: The second paragraph of the Discussion section has been reworded accordingly. Conclusions I think the authors should revise the statement related to the detected compounds in the n-hexane partition and active fractions. I recommended to add further study such as isolation of compound from the active fractions. Response to reviewer: The Conclusion section has been rephrased. Technical n-hexane and n-butanol: the alphabet “n” should be written in italic (n-hexane, n-butanol, n-Hex, n-BuOH). Please give a space between number and unit. For example, 20 g instead of 20g. Please add a comma before the word \"whereas\". For example: \"_______, whereas\". The term “GC-MS” should be written consistently either as “GC-MS” or “GC/MS”. The abbreviation of litre should be written as “L” in capital letter. Response to reviewer: Corrections have been made accordingly."
}
]
}
] | 1
|
https://f1000research.com/articles/10-398
|
https://f1000research.com/articles/11-55/v1
|
18 Jan 22
|
{
"type": "Correspondence",
"title": "Ethnic differences in names in China: A comparison between Chinese Mongolian and Han Chinese cultures in Inner Mongolia",
"authors": [
"Yuji Ogihara"
],
"abstract": "I propose two suggestions on Stojcic et al.’s (2020) Study 3, which examined ethnic differences in individualism between Chinese Mongolian and Han Chinese cultures in China. The authors analyzed the names of all residents in the Inner Mongolia Autonomous Region of China and found that the percentages of common names among Chinese Mongolians were smaller than those among Han Chinese. The authors concluded that Chinese Mongolians are more independent than Han Chinese. However, two questions remain unanswered. First, although the authors analyzed the names of people in all age groups together and did not analyze the names by birth year, how was the effect of time controlled? Second, although the authors treated name indices, which have been used as group-level indicators in previous research, as individual-level indicators, how did the authors confirm whether name indices can be used as individual-level indicators? Addressing these two questions would contribute to a better understanding of ethnic differences in individualism in China.",
"keywords": [
"ethnic difference",
"name",
"China",
"Mongol",
"individualism",
"culture",
"uniqueness",
"cultural change"
],
"content": "1. How was the effect of time controlled?\n\nThe authors calculated the percentages of the top 1, 10, and 20 most common names by ethnic group and found that those among Chinese Mongolians were smaller than those among Han Chinese.1 They concluded that Chinese Mongolians are more independent than Han Chinese.\n\nHowever, the names of people in all age groups were analyzed together and were not analyzed by birth year. Although the specific age span of the population was unclear, they wrote that “we included data for Chinese Han and Mongolian living in the same area, i.e., the region of Inner Mongolia, over the span of some 60 years” (p. 7). A name of a person aged 60 years indicates naming behavior approximately 60 years ago. Thus, naming behaviors for more than 60 years were included in the data. This approach is problematic for comparison between ethnicities for at least four reasons.\n\nFirst, the authors’ analyses did not exclude the possibility that the differences stemmed from the naming behaviors at different time points rather than ethnic differences at a specific time point. In other words, the authors’ analyses may not have compared the behaviors at the same time point. Considering that a prior study insisted that unique names increased over time in China (Cai et al., 2018; but also see Ogihara, 2020b), this confounding could have affected the results. For example, younger people who have unique names may have been included in the analyses more in Chinese Mongolians than in Han Chinese. This may have caused the result that the percentages of the common names among Chinese Mongolians were smaller than those among Han Chinese. Moreover, distribution of age may have differed between the two ethnic groups.\n\nSecond, it is unclear what the indicators mean. The authors calculated the percentages of the top 1, 10, and 20 most common names over a period of more than 60 years rather than the common names by year. However, common names can drastically change over time. It is possible that common names 60 years ago are no longer common in the present. The meaning of common names in a given year is clear, but the meaning of names common over a period of more than 60 years is ambiguous.\n\nThird, the analyses contradicted the authors’ claim that past sustenance styles (Mongolian: herding, Han Chinese: farming) affect “present” psychological tendencies (Mongolian: independence/individualism, Han Chinese: interdependence/collectivism). The authors emphasized present psychological tendencies, but they examined past psychological tendencies from more than 60 years ago.\n\nFourth, Study 3 examined different constructs than those in Studies 1 and 2. The authors stated that “in order to furthermore increase the ecological validity of the current research, in Study 3 we tested our hypothesis in real life setting by investigating the baby naming practices between the Chinese Han and Mongolian” (p. 6). However, in Study 3 the authors analyzed indicators for over 60 years, which was inconsistent with Studies 1 and 2, in which the authors measured psychological tendencies in recent years.2\n\nAll of the previous studies that the authors cited in the article controlled this effect by analyzing indicators by year (Ogihara et al., 2015; Twenge et al., 2010) or at the specific year (2007; Varnum & Kitayama, 2011). Thus, analyzing data in recent years (preferably the year when the data were collected in Studies 1 and 2) addresses all four concerns.\n\nThe authors should at least explain how these concerns were addressed. Although the authors stated that “since the age did not differ between two ethnic groups, it is quite probable that the age would not moderate the observed tendencies” (p. 9), the authors did not have data on age.3 It is unclear how the authors concluded that the age would not moderate the observed tendencies. Moreover, as stated above, the issue is not only about the group difference in the average age.\n\n\n2. Can the name index be used as an individual-level indicator?\n\nThe authors treated the name indices as individual-level indicators reflecting personal inner characteristics. In presenting the results, they used the term “social cognition” throughout the text and “cognitive tendencies” (p. 10). Moreover, the authors suggested that Study 3 increased the “ecological validity” (p. 6) of the findings in Studies 1 and 2, which measured individual-level psychological tendencies.\n\nHowever, the previous research the authors cited regarded name indices as group-level indicators that reflect group (e.g., nation, state, and culture) characteristics (Ogihara et al., 2015; Twenge et al., 2010; Varnum & Kitayama, 2011). Because names can be determined by several individuals, such as couples, family members, and community members, naming involves a collective process of decision making. Thus, naming does not necessarily reflect individual psychology and behavior. For example, a husband may suggest a name, but his wife may reject it and choose a different name based on her mother’s advice. In this case, the husband’s psychology and behavior are not reflected in the name. Mongolians may ask lamas and/or elders to name their children. Thus, Studies 1 and 2 and Study 3 treated concepts at different levels. The authors should explain how they confirmed whether the name indices can be used as individual-level indicators. This level of concept (unit of analysis) is important when examining the relationship between culture and psychology (e.g., Cohen & Varnum, 2016; Schwartz, 2014; Vu et al., 2017).\n\n\nConclusion\n\nI have proposed two suggestions on Stojcic et al. (2020). I hope these suggestions will contribute to a better understanding of ethnic differences in names, psychology, and culture.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nCai H, Zou X, Feng Y, et al.: Increasing need for uniqueness in contemporary China: Empirical evidence. Front. Psychol. 2018; 9: 554. PubMed Abstract | Publisher Full Text\n\nCohen AB, Varnum ME: Beyond East vs. West: Social class, region, and religion as forms of culture. Curr. Opin. Psychol. 2016; 8: 5–9. PubMed Abstract | Publisher Full Text\n\nOgihara Y: Characteristics and patterns of uncommon names in present-day Japan. J. Hum. Environ. Syst. 2015; 13: 177–183. Publisher Full Text\n\nOgihara Y: The change in self-esteem among middle school students in Japan, 1989-2002. Psychology. 2016; 7: 1343–1351. Publisher Full Text\n\nOgihara Y: Temporal changes in individualism and their ramification in Japan: Rising individualism and conflicts with persisting collectivism. Front. Psychol. 2017a; 8: 695. PubMed Abstract | Publisher Full Text\n\nOgihara Y: Temporal changes in pay-for-performance systems in Japan: A decrease in seniority systems and an increase in annual salary systems (1991-2016). Studies in Science and Technology. 2017b; 6: 149–158. Publisher Full Text\n\nOgihara Y: Economic shifts and cultural changes in individualism: A cross-temporal perspective. Uskul A, Oishi S, editors. Socioeconomic environment and human psychology: Social, ecological, and cultural perspectives. Oxford: Oxford University Press; 2018a; (pp. 247–270). Publisher Full Text\n\nOgihara Y: The rise in individualism in Japan: Temporal changes in family structure, 1947-2015. J. Cross-Cult. Psychol. 2018b; 49: 1219–1226. Publisher Full Text\n\nOgihara Y: Baby names in Japan, 2004-2018: Common writings and their readings. BMC. Res. Notes. 2020a; 13: 553. Publisher Full Text\n\nOgihara Y: Unique names in China: Insights from research in Japan—Commentary: Increasing need for uniqueness in contemporary China: Empirical evidence. Front. Psychol. 2020b; 11: 2136. Publisher Full Text\n\nOgihara Y: Direct evidence of the increase in unique names in Japan: The rise of individualism. Current Research in Behavioral Sciences 2021a; 2: 100056. Publisher Full Text\n\nOgihara Y: How to read uncommon names in present-day Japan: A guide for non-native Japanese speakers. Frontiers in Communication. 2021b; 6: 631907. Publisher Full Text\n\nOgihara Y: I know the name well, but cannot read it correctly: Difficulties in reading recent Japanese names. Humanit. Soc. Sci. Commun. 2021c; 8: 151. Publisher Full Text\n\nOgihara Y: Common names decreased in Japan: Further evidence of an increase in individualism. Experimental Results. 2022a; 3: 1–13. Publisher Full Text\n\nOgihara Y: Common writings of baby names in Japan, 1989-2003: Explanation of survey data. Data Brief. 2022b; 40: 107678. Publisher Full Text\n\nOgihara Y: Further explanations for difficulties in reading recent Japanese names correctly. Frontiers in Education. 2022c; 6: 799119. Publisher Full Text\n\nOgihara Y, Fujita H, Tominaga H, et al.: Are common names becoming less common? The rise in uniqueness and individualism in Japan. Front. Psychol. 2015; 6: 1490. Publisher Full Text\n\nOgihara Y, Uchida Y, Kusumi T: Losing confidence over time: Temporal changes in self-esteem among older children and early adolescents in Japan, 1999-2006. SAGE Open. 2016; 6: 1–8. Publisher Full Text\n\nSchwartz SH: Rethinking the concept and measurement of societal culture in light of empirical findings. J. Cross-Cult. Psychol. 2014; 45: 5–13. Publisher Full Text\n\nStojcic I, Wei Q, Ren X: Historical sustenance style and social orientations in China: Chinese Mongolians are more Independent than Han Chinese. Front. Psychol. 2020; 11: 864. Publisher Full Text\n\nTwenge JM, Abebe EM, Campbell WK: Fitting in or standing Out: Trends in American parents' choices for children’s names, 1880–2007. Soc. Psychol. Personal. Sci. 2010; 1: 19–25. Publisher Full Text\n\nVarnum ME, Kitayama S: What’s in a name? Popular names are less common on frontiers. Psychol. Sci. 2011; 22: 176–183. Publisher Full Text\n\nVu TV, Finkenauer C, Huizinga M, et al.: Do individualism and collectivism on three levels (country, individual, and situation) influence theory-of-mind efficiency? A cross-country study. PLoS ONE. 2017; 12: e0183011. Publisher Full Text\n\n\nFootnotes\n\n1 It is necessary for the authors to explain why they conducted statistical hypothesis testing even though they had all data on the populations (all names of Chinese Mongolian and Han Chinese residents of the Inner Mongolia).\n\n2 Similarly, there is another inconsistency between Studies 1 and 2 and Study 3: age group. In Studies 1 and 2, the authors collected data from university students. However, in Study 3, the authors collected data from all age groups who engaged in naming, and thus, their ages were unclear (not limited to the same age group as that in Studies 1 and 2). The pattern of ethnic difference might differ across age groups.\n\n3 I asked the corresponding author whether the authors had data on the ages of name holders. The author replied that they did not."
}
|
[
{
"id": "120385",
"date": "14 Feb 2022",
"name": "Ivana Stojcic",
"expertise": [
"Reviewer Expertise Cultural and social psychology",
"differences in individualism and collectivism"
],
"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 the Ethnic differences in names in China: A comparison between Chinese Mongolian and Han Chinese cultures in Inner Mongolia—Commentary, the author poses two main questions i.e. the issue of time control in baby names analyses and the issue of the unit level analysis, and a minor question related to inferential statistics. The main central concern of the time control in baby naming practices is subdivided into following questions: control of confounding factors, the true meaning of indicators, past vs. present sustenance styles, and use of different study approaches, i.e. the analysis of data over a period of 60 years vs. 1 year.\n1. How was the effect of time controlled?\nWhen discussing the issue of the lack of time control in baby name analyses, it is important to note that it was initially recognized and pointed out in the Limitations section of the published manuscript Historical sustenance style and social orientations in China: Chinese Mongolians are more Independent than Han Chinese, albeit in less detail compared to the arguments raised in this Commentary. The following was stated considering this issue: “… while we followed the recommendation of Twenge’s and Varnum’s method (Twenge et al., 2010; Varnum and Kitayama, 2011), there’s one difference between our approach and theirs. We used the most common names for the population not at 1 year. Nonetheless, since the age did not differ between two ethnic groups, it is quite probable that the age would not moderate the observed tendencies. Future studies should address this issue to further verify our findings and provide more detailed insight into reported tendencies.”1\nOgihara makes a good point in arguing that analyses performed in Study 3 did not exclude the possibility for observed differences in name giving practices to derive from other confounding factors rather than ethnic differences. Unlike previous studies, which analyzed the respective changes in name practices by decade or per year,23 we analyzed the baby naming practices for a period of some 60 years, thus blending other potential confounding factors such as age and generation. While our approach fails to provide insight into changes in the naming practices throughout decades, it still gives valuable contribution to the research question we wanted to explore.\nFurthermore, the author questions the meaning of the presented indicators, i.e. top 1, 10 and 20 most common names calculated against the period of 60 years, by arguing that common names can drastically change over time and that common names 60 years ago may no longer be considered as common in the present, and the meaning of such indicator may be somewhat ambiguous. While we agree with the author’s statement that names can change over time, and that more precise data would be obtained with analyzing naming practices in one given year, as previously stated, this change in name practices is not usually as drastic as the author suggests. In fact, previous studies have shown that preferences that become quickly popular also tend to lose that same popularity very fast, and this trend has also been observed in naming practices where names that quickly gained popularity, died faster and were less likely to persist.4 Further support for this premise comes from baby naming practices in Croatia, where according to available statistical data (see here), the 1st most common male and female names, which were respectively Ivan and Marija, remained unchanged for 4 decades, i.e. since 1929 – 1959, after which they dropped to 3rd and 5th place, respectively, with male name Ivan re-gaining the 1st place in 1980 – 1999. Consequently, it is reasonable to assume that an indicator composed of 60 years of name giving practices still reveals valuable data on behavioral tendencies and orientation toward individualism/collectivism.\nAgain, related to the use of data roughly covering a period of 60 years, Ogihara suggests that we contradicted ourselves by arguing that past sustenance styles affect “present” independence/interdependence (individualism/collectivism) but then proceed with examining past psychological tendencies from more than 60 years ago. We assume that the author misunderstood what we tried to say, as previous studies have shown that cultural differences based on historical subsistence style continue into the modern era, even in areas where most people no longer engage in the traditional subsistence activity but work in modern industry.5 By using data that comprise a period of 60 years, we provide full support for what we argue for, as these data do not cover specific time point 60 years ago but are comprehensive of six decades to the present day, thus reflecting recent and current behaviors. Furthermore, even if for example we solely focused on year 1960, our reasoning would still be correct as historical subsistence style refers to subsistence patterns dating back far beyond the past century.6\nFinally, we fully support the Ogihara’s suggestion that it would be more precise to analyze only name indicators for recent years as was done in previous studies that used name giving practices as indicators of individualism,72 which here was not possible due to lack of available data stratified by year. Nonetheless, when interpreting reported finings, it is also important to consider that examined ethnic groups were in similar age groups and generations, which may somewhat decrease the possibility of confounding during this period. Furthermore, both of these ethnic groups underwent very similar social and political changes, which also ensured certain kind of control over a variety of confounding factors, but naturally not all. In a different study that used the percentage of most common names for the period 1981-2010 to explore the spatial-temporal changes in individualism, the uniqueness among the provinces followed the similar changing pattern along the year, which was also consistent with the results reported for prefectures in Japan and States in US.8 These data suggest that the time would not have such a strong effect on provincial differences to reverse the observed direction and differences between groups.\nFuture studies should investigate the name giving practices within the same year, as this is the most precise and correct approach for calculating the individualism indicator. We are also open to the idea of changing and revising our conclusion and rejecting our hypothesis if new refined evidence, inconsistent with our findings, should emerge. However, the present results that were based on available data seem to suggest that the current hypothesis is the most possible explanation to the subject matter under consideration.\n2. Can the name index be used as an individual-level indicator?\nWhen discussing the second main concern raised by Ogihara, it is necessary to clarify few things. First, the phrase “increase the ecological validity” was meant to say that as the results from Study 3 were reflection of real life behavior, they had greater ecological validity compared to the results reported in Study 1 and Study 2. We assume that Ogihara focuses on ecological validity, as he was expecting behavioral tendencies toward individualism/ collectivism to be measured by an indicator in real setting similar to symbolic self-inflation used in Study 1 and 2. In view of this assumption, the Study 3 is not perfectly designed, but is definitely relevant to the overall research. The chosen methodology, i.e. the percentage of most popular name, is undoubtedly an indicator of uniqueness, which is one the facets of individualism.9 While uniqueness is not perfect equivalent to self-inflation, some items of the Singelis’ self-construal scale used to measure self-inflation in Study 1 and 2, focus on uniqueness, e.g. “I enjoy being unique and different from others in many respects”. We admit that this is not optimum connection; nonetheless, it is relevant one.\nIn addition, Ogihara argues that naming practices do not reflect individual psychology or behavior at individual level as they may result from a collective process that includes babies’ parents and extended kinship. We agree with Ogihara’s view to a certain extent, considering that baby naming practices are usually the results of the collective decision between minimally two people. Nonetheless, each one of these individuals participating in such a decision is also motivated to give or suggest a common or unique name him/herself. As stated by Ruth Fulton Benedict \"culture is personality writ large\".10 While naming practices provide valuable source of information that mirror parents’ values or orientations, thus making them suitable behavioral measure encompassing important choices and decisions of parents,7 they are also a valuable cultural product, which can successfully reveal societal orientation tendencies, as well as cultural change.237 In fact, even though group differences occur because individuals are motivated to strive for uniqueness, thus lowering the percentage of common names3 as groups are made up of individuals, and as there are reciprocal influence processes between individuals and bigger groups, it is impossible to consider one, without the other.11\nWe also assume that the author was concerned with the potential issue of ecological fallacy.1211 In general, there’s risk of ecological fallacy when differences observed at individual level are simply translated to explain differences at group level, and vice versa. For example, when one takes a relationship that has been established between two or more variables at one level of analysis and then assumes that this proves something at a different level of analysis.11 However, considering the baby name practices, it can be assumed or implied that the same motivation underlies the uniqueness at individual level and group level. If each individual in one cultural group is generally motivated to be unique or stand out from the whole group, this would increase the number of uncommon baby names at individual level, which would eventually result in the low percentage of the common names. Likewise, if each individual in other cultural group is generally motivated to be similar with others and to fit in the group, he/she would be inclined to give the baby a common name at individual level, which would eventually result in high percentage of most common names. In fact, few scholars have also developed alternative indicators of uniqueness related to baby naming practices following the same logic. E.g., in Japan, Chinese characters are used to name babies; however, they can be diversely pronounced. Ogihara constructed the indicator of uniqueness based on uncommon pronunciation of a Chinese character, and used it to explore the changes in uniqueness trends in Japan (Ogihara).713 Cai also constructed the indicator of uniqueness based on the frequency of Chinese characters in names and used it to explore the changes in uniqueness trends in China.14 He also constructed a uniqueness of nickname in Sina weibo based on the use of non-Chinese characters to explore the provincial differences in individualism within China.15 Ogihara furthermore used dog naming practices to evaluate whether Japanese culture became more individualistic.16 As our main intent was to explore the Mongolian/Han differences in individualism/ collectivism through different indicators, our research was a combination of three different studies, and more importantly all of our assumptions were based and backed by relevant results.\nFinally, with reference to the issue of the use of inferential statistics test, we agree with Ogihara that inferential statistics test is not necessarily required when population is used instead of sample, and as we used the entire population of Inner Mongolia autonomous zone in the present study, it was not necessary to use inferential statistics. In fact, the first draft of the manuscript did not include the inferential statistic, which was subsequently included following the suggestion of one of the reviewers. Nonetheless, as inferential statistics generated consistent results, they were not further discussed.\nConclusion\nTo sum up, we fully agree with Ogihara’s suggestion that future studies should investigate the name giving practices within the same year so as to further validate reported findings. As previously stated, we are also open to the idea of changing and revising our conclusion and rejecting our hypothesis if new refined evidence, inconsistent with our findings, should emerge. However, the present results that were based on available data seem to suggest that the current hypothesis is the most possible explanation to the subject matter under consideration.\n\nIs the rationale for commenting on the previous publication clearly described? Yes\n\nAre any opinions stated well-argued, clear and cogent? Partly\n\nAre arguments sufficiently supported by evidence from the published literature or by new data and results? Partly\n\nIs the conclusion balanced and justified on the basis of the presented arguments? Partly",
"responses": []
},
{
"id": "120384",
"date": "09 Mar 2022",
"name": "Kenta Tsukatsune",
"expertise": [
"Reviewer Expertise Onomastics",
"social 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\nGeneral Evaluation\n\nOverall, the reviewer can mostly agree with arguments of this paper. Author Ogihara's discussion about the analysis in Study 3 of Stojcic et al.'s (2020) paper on how to handle cohort/age groups, and relationships of the individual and group indicators are both acceptable.1 The reviewer also has read the original paper, and as the author points out, particularly analytical confusion and ambiguity in definitions of generation and time series are noticeable in Study 3. Names from a wide range of different age groups are lumped together and compared, when careful handling of birth years is fundamentally important in name data, and the chronological relationship between phenomenon of individualization and appearance of names (the birth year of a person) is treated carelessly. The reviewer does not think it is necessary to change the author's points themselves, and is fine with the relatively favourable wording for the original paper (\"Addressing these two questions would contribute to a better understanding...\").\n\nHowever, there are some important issues as well as the two aforementioned issues that are not pointed out in this paper. The following contents are mainly not inadequacies in this paper, but the original paper, but these matters can be included in this paper to enhance its validity. If there are any of the following items that the author agrees with, the reviewer would like to have them included partly, even if they are not all of them.\n\nStudy 3 of the original paper leaves many questions unanswered in terms of cultural differences in language and naming. In particular, there are issues related to differences in ideographic and phonetic scripts, and the relationship between names of ethnic minorities including Inner Mongolia and culture of Han Chinese. This is not to argue that it is inappropriate to make comparisons, but rather that we should carefully examine the basis for whether comparisons can be made. Without much consideration of the assumptions, the original paper talks about comparing names as an extension of the analysis of psychological questionnaire (generally, variables obtained from questionnaire are much more comparable than variable of names).\n\nAbout letters used to write languages\n\nThe author of this paper has himself done careful research on the differences between ideographic and phonetic naming systems, and the reviewer hopes that the author will include this point (and that it is at least an unavoidable issue in discussion about the control of age groups).\n\nFirst, an important feature of Han Chinese naming is that in addition to the vocabulary that the name itself indicates as a single lump of words, the component Chinese characters often have unique meanings (while English names are less clearly aware of the elements that make up the word), and Chinese characters themselves are ideographic. On the other hand, Inner Mongolian naming is considered to have inherited culture of Mongolian language and nomenclature. It can be said that Chinese Mongolians apply Chinese characters to names derived from their phonetic character culture. In this regard, a full explanation from a linguistic point of view should be given as to whether the changes in names of Mongolians can be compared with those of Han Chinese, which have been formed by ideographic character culture (even if we take into account the fact that Mongolians in China also partly adopt the same naming methods as Han Chinese). If we compare this to studies of names in the English-speaking world, when a comparison is made between European-Americans and African-Americans, the two groups are compared on basis of a common linguistic foundation of naming according to English, even though they have various different cultural backgrounds. In contrast, names of the two groups mentioned in the original paper (Tables 5 and 6) seem to be two groups with distinctly different language systems, and it is difficult to consider them without a linguistic explanation. Also, in terms of the number of characters (number of Chinese characters), Mongolian names are longer, and the reviewer wonders if those changes can be treated in the same way as the changes in Han Chinese names, which usually consist of one or two characters.\n\nAbout relationships between ethnic groups and their naming systems\n\nNext, the reviewer would also like to point out that the relationship between ethnic minorities and ethnic majorities should be carefully examined. Naming system themselves, as well as housing policies and economic means, are prone to political and legal changes, and influenced by relationships between ethnic groups. Between groups that follow the same system, comparisons of individualization could be made, comparing names from different generations or different ethnicities. However, in the case of Inner Mongolians and Han Chinese, it is not clear whether the underlying systems themselves are similar enough to be lined up immediately, or whether, if there is heterogeneity, the analysis in the original paper has been able to control for it.\n\nTo the best of the reviewer's knowledge, original naming systems of the two cultures are considered to be very different. Han Chinese naming system consists of a general first name and a family name, while Mongolian culture uses the father's name in a position like a family name, alongside first name. And, in the case of Inner Mongolians, complications exist in the process of deciding what to adopt as the first and last name on resident registration using Chinese characters. It seems that some people have two names, one in Han Chinese style and the other in Mongolian style, and then register one of them officially. There are also cases where only a part of the Mongolian-derived name is used as a family name. There are variations in the explanations in different literature and articles, but in any case, whether Mongolian baby names are equivalent to Han Chinese baby names after registration must be thoroughly discussed. For example, even if names are becoming more personalized, there may be not only differences in the degree of personalization itself, but also problems that do not exist in the Han Chinese, such as how to use Chinese characters for pronunciation and which part of the name should be used as the family name.\n\nThe following literature briefly explains the linguistic differences between Mongolian and Chinese names. Yunshaab, S. (2019), “Survey of Natural Language Processing for Vertical Mongolian: Current Situation,” Status of NLP for Vertical Mongolian, Report 1, viewed 1 March 2022(2, DOI: 10.5281/zenodo.4536516)\n\nThe following literature explains dual name practices. It also shows that there are differences in the use of Han Chinese style names depending on friendships, generation, gender, social class, etc.3\n\nThe following web page provides explanations of personal names in Inner Mongolia by a number of experts and people who have lived there (Link, Viewed 1 March 2022).\n\nAbout chronological changes in naming\n\nThe above discussion on writing systems and lexicon, and the relationships of ethnic groups is not unrelated to the author's point about cohort/age group. For example, in Han Chinese, a particular Chinese character is often used in a particular cohort, but is there a corresponding phenomenon in names of Inner Mongolians? If such a phenomenon does not exist, or if it does exist but it is linguistically completely different from the case of Han Chinese, which are based on ideographic characters, then we must first discuss the comparability of the two. And, as for the names of Inner Mongolians, is it not possible that Han Chinese style names are increasing as generations progress?\n\nAbout research methods for variables and indicators by levels\n\nIt seems to the reviewer that the current state of this paper is sufficient for pointing out about the indicators of individual-level and group-level. However, if there is room in the paper, can the author suggest some improvements? What about suggestion of calculating correlations between variables at individual level, or between variables at group level? For example, several studies in Europe and the United States have conducted analyses that link characteristics of individual names with the psychological and behavioural characteristics of the individuals. It would be possible to keep only characteristics of the name (for example, whether the name is in the top ranking or not) as a variable and analyse the relationship between it and psychological characteristics of the person. On the other hand, if names are to be used only as group indicators, it would be possible to create more detailed group indicators for each region, and calculate the correlation of the indicators for individualism and settlement in each region with the trend of names in that region.\n\nFinally, let me make it a condition for this paper to pass that the author must include one or more remarks, in some form or another, about the lack of linguistic explanation (can we really compare Han and Mongolian names?) in the analysis of the original paper. I think this is something that must be included as a point against the handling of the data set, and this is a topic that is closely related to the topic of age groups. Also, I would like to see the ethnic relations included, but it is not a requirement.\n\nIt is not necessary to include all of my suggestions, and the author can use his own ideas on the matter. However, a handling of these issues would substantially improve the quality of the paper.\n\nIs the rationale for commenting on the previous publication clearly described? Yes\n\nAre any opinions stated well-argued, clear and cogent? Partly\n\nAre arguments sufficiently supported by evidence from the published literature or by new data and results? Yes\n\nIs the conclusion balanced and justified on the basis of the presented arguments? Partly",
"responses": []
},
{
"id": "143438",
"date": "18 Jul 2022",
"name": "Han-Wu-Shuang Bao",
"expertise": [
"Reviewer Expertise Cultural psychology",
"Cultural change",
"Individualism",
"Name",
"China"
],
"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 the correspondence article, Ogihara raised two concerns about the validity of Stojcic et al.’s (2020) Study 3, which suggested that Chinese Mongolian (vs. Han Chinese) were more independent as they were less likely to give the top 1, 10, and 20 common names to babies.1 I have conducted several studies on Han Chinese names, including one that confirms the increasing prevalence of unique names in China over 1920 to 2005 (Bao et al., 2021).2 I also have carefully read the original article by Stojcic et al. (2020), the correspondence by Ogihara, and the other two reviewers’ insightful comments on this correspondence. In general, I agree with the two points proposed by Ogihara as well as most of the other two reviewers’ opinions. In my review report here, I first provide my further consideration of Ogihara’s two points and then propose three additional concerns about the original article. I hope my additional thoughts, together with Ogihara’s two important suggestions, would contribute to an even better understanding of both the cultural differences and the cultural changes of personal names, either within China or between countries.\nFurther Consideration of Ogihara’s Two Points\nStojcic et al.’s (2020) Study 3 used an invaluable name database of the whole population of Chinese Han and Mongolian in the Inner Mongolia Autonomous Region of China. They computed the percentage of the most common first names given to each ethnic group separately by gender. However, as Ogihara pointed out, they did not control for the effect of birth cohort. Evidence has shown that Chinese names are becoming more unique over birth cohorts from 1920 to 2005 (Bao et al., 2021). If they could access a dataset with birth year information for each individual (e.g., the 2005 China’s 1% Population Census, which I have used in my previous study; Bao et al., 2021), then this issue would be well addressed. Nonetheless, please also see the next section for my additional concerns, which suggest that even though the time effect was addressed, such a direct comparison between Han Chinese names and Chinese Mongolian names might be problematic.\nOgihara’s second point concerns the level of analysis. I fully agree that the percentage of common names (hereinafter referred to as “PCN” for simplicity) is a group-level (rather than individual-level) index that has usually been utilized to study macro-level cultural changes (e.g., Twenge et al., 2010).3 However, my own reading of the original article shows that they actually regarded PCN as “a national or cultural indicator of individualistic/collectivistic tendencies” (p. 6; Stojcic et al., 2020), which is appropriate. Thus, I don’t think this point of criticism is much necessary and to the point, though conclusions should of course be drawn with caution.\nInstead of limiting our discussion to these two concerns, I would like to share my three additional concerns about the original article. I hope both Ogihara’s and my concerns would facilitate the understanding of both cross-cultural differences and cross-temporal changes of names.\nThree Additional Concerns About the Original Article\n(1) The percentage of common names (PCN) is not a proper index for Han Chinese names\nFirst, before we discuss “Can the name index be used as an individual-level indicator?”, we have to ask “Can the name index be used as a group-level indicator?” In particular, is PCN a generally appropriate index to measure group-level name uniqueness? The answer is no. Twenge et al. (2010) validly measured English name uniqueness by the percentage of uncommon first names; Ogihara et al. (2015)4 validly measured Japanese name uniqueness by the percentage of uncommon pronunciations paired with a Chinese character; Bao et al. (2021) validly measured Han Chinese name uniqueness by the name-character uniqueness in naming practice (negative log-transformed character frequency). Since naming norms vary substantially between cultures and languages, we have to use distinct measures to capture the uniqueness of names for a specific culture or language.\nFor instance, PCN might not be a valid index of Han Chinese name uniqueness, because Han Chinese are allowed to use any single Chinese character, any reasonable combination of two characters, or even a possible combination of three characters to name their babies (Bao et al., 2021). In this case, Han Chinese names are not simply “selected” from an established name list, but rather “created” by combining different Chinese characters. Therefore, name-character uniqueness of a character combination reflects people’s psychological pursuit of uniqueness and is more proper to capture Han Chinese name uniqueness (Bao et al., 2021; Cai et al., 2018).7 In contrast, English first names have a finite option list for people to select from, thus PCN is appropriate to measure English name uniqueness (Twenge et al., 2010). Meanwhile, a Japanese name can be paired with different pronunciations, which is a special naming norm that exists neither in China nor in English-speaking countries. Hence, pronunciation uniqueness is a specifically valid index of Japanese name uniqueness (Ogihara et al., 2015).\nIn short, name-uniqueness indices are distinct, and thus not comparable, between cultures and languages. The PCN index used in Stojcic et al.’s (2020) Study 3 is valid to measure English name uniqueness but not so for Han Chinese names. Indeed, my unpublished data indicate that the PCN of Han Chinese names (combinations) showed a “decreasing-increasing-decreasing” pattern between 1930 and 2008, and the PCN reached the highest in the 1980s. Together with the changing pattern of name length (Bao et al., 2021), this merely suggests that more Han Chinese in the 1980s were given single-character (vs. multi-character) names (e.g., “伟”, “强”, “静”, “娜”; see also Tables 5 and 6 in Stojcic et al., 2020). The use of single-character names increases the level of PCN but does not necessarily suggest a preference for common or uncommon Chinese characters. For Han Chinese names, PCN largely depends on the number of characters in a given name, and thus is not much indicative of name uniqueness in a psychological sense (e.g., a psychological need for uniqueness).\n(2) PCN cannot be used for cross-cultural comparisons\nSecond, we move our focus to the comparison between Han Chinese and Chinese Mongolian names. The most common Mongolian names listed in the Tables 5 and 6 in Stojcic et al. (2020) were paired with pinyin (i.e., Han Chinese pronunciation). However, a Mongolian name written in Han Chinese characters is just a translated form based on its Mongolian pronunciation (i.e., transliteration). Thus, each Chinese character in a translated Mongolian name no longer has its own meaning, but rather should be considered with other characters to obtain the meaning in Mongolian. For example, the Mongolian name “乌兰图雅” actually consists of two indivisible words “乌兰” (which means “red” in Mongolian) and “图雅” (which means “sunglow” in Mongolian). In contrast, the corresponding Han Chinese name with the same meaning is “红霞”, which consists of two indivisible Chinese characters “红” (red) and “霞” (sunglow). Such linguistic differences constitute a critical factor that makes the PCN less comparable between these two ethnic groups.\nFurthermore, PCN is not comparable between cultures in general. For example, Twenge et al. (2010) showed that the PCN of the top 10 American boy names in 1950 was about 33% (see their Figure 1 at p. 21), whereas Su et al. (2016) found that the PCN of the top 10 Han Chinese boy names in 1950 was 18% (see their Table 3 at p. 35).5 Could we therefore conclude that Han Chinese were more independent than American in 1950? Moreover, for the span of about 1950~2007, Twenge et al. (2010) showed the American boys top 10 PCN = 8~33% and the American girls top 10 PCN = 8~23% (see their Figure 1 at p. 21); in contrast, for “the span of some 60 years” (presumably 1950~2008), Stojcic et al. (2020) found the Han Chinese boys top 10 PCN = 4.18% (see their Table 5) and the Han Chinese girls top 10 PCN = 4.88% (see their Table 6). Obviously, Han Chinese were in general much less given “common names” than American. Is it thus reasonable to conclude that Han Chinese were more independent than American over the second half of the 21st century?\nIn sum, it might be problematic to use PCN as an indicator of name uniqueness regardless of culture and then use it for cross-cultural comparisons. PCN can hardly capture the uniqueness of Han Chinese names, because Han Chinese names are much more complex than English names and could be more validly measured by using the name-character uniqueness (Bao et al., 2021).\n(3) Pursuing uniqueness is conceptually different from being independent\nFinally, I would like to differentiate between the concepts of uniqueness, independence, and individualism. According to Oyserman et al. (2002),6 individualism and collectivism are both multi-faceted constructs; “independent” and “unique” are two parallel domains of individualism. That is, being unique is different from being independent, though both indicate being individualistic. While “independence” highlights relying on oneself and being self-sufficient, “uniqueness” emphasizes seeking a distinctive identity and being different from others. Therefore, unique-naming practices are only indicative of the “uniqueness” domain/facet of individualism, but not indicative of the “independence” domain/facet. My unpublished data further showed that the cultural-level increase in name-character uniqueness in China can be specifically explained by the cultural-level emphasis on “uniqueness” (rather than “independence”). To this end, the group-level index of name uniqueness may be only regarded as an indicator of the uniqueness facet of individualism, instead of an over-generalized indicator of the other facets of individualism (e.g., independence, competition, autonomy, etc.).\nTaken together, the above three concerns, along with Ogihara’s two suggestions, may help us understand some nuances (1) between uniqueness and independence, (2) between different name-uniqueness indices for different cultures/languages, (3) between group-level and individual-level indicators, and (4) between Han Chinese and Chinese Mongolian names. I hope all these critical but constructive thoughts will advance the cultural psychological research using names as an index.\n\nIs the rationale for commenting on the previous publication clearly described? Yes\n\nAre any opinions stated well-argued, clear and cogent? Partly\n\nAre arguments sufficiently supported by evidence from the published literature or by new data and results? Partly\n\nIs the conclusion balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/11-55
|
https://f1000research.com/articles/11-54/v1
|
17 Jan 22
|
{
"type": "Research Article",
"title": "Forecasting electricity consumption of Malaysia’s residential sector: Evidence from an exponential smoothing model",
"authors": [
"Izzaamirah Ishak",
"Nor Salwati Othman",
"Nor Hamisham Harun",
"Nor Salwati Othman",
"Nor Hamisham Harun"
],
"abstract": "Background: In Malaysia, residential electricity consumption has shown a steady upward trend year by year. Due to this increase in energy consumption, it is important to forecast the value of electricity consumption until the year 2032 to accommodate the electricity demand. Methods: Three exponential smoothing models were compared to identify the most appropriate model in forecasting electricity consumption. The three exponential smoothing models are Simple, Holt, and Brown exponential smoothing. To identify the most appropriate model, a mean absolute percentage (MAPE) was chosen. Results: The results show that Holt’s exponential smoothing has the best performance with the lowest MAPE score of 2.299. Conclusions: Consequently, it was found that electricity consumption would substantially increase from 2647 ktoe (kilotonne of oil equivalent) to 3873 ktoe within the period of 2019 to 2032.",
"keywords": [
"forecasting",
"electricity consumption",
"exponential smoothing",
"time series"
],
"content": "Introduction\n\nIn Malaysia, energy is no longer viewed as a luxury as it is becoming a necessity in our everyday activities such as in transportation, production, commercial activities, and residential anthropogenic activities.1 Energy consumption in residential sectors grew up to 7% within the period 1978 to 2015.2 As one of the countries with the highest recorded energy per capita and energy intensity over the years, electricity is considered as an important form of energy which drives Malaysia’s economic development.3,4 The Malaysia Energy Information Hub (MEIH) revealed that electricity consumption for the residential sector in 2018 was 2553 ktoe (kilotonne of oil equivalent), which is a slight decrease from 2017 with 2610 ktoe. However, in 2017 the World Energy Markets Observatory (WEMO) reported that electricity consumption is projected to increase by 4.8% annually up to 2030.\n\nThus, it is important to conduct a forecast of electricity consumption as it is significant for economic development as well as policy improvement.5,6 As a reliable and an important tool for making decisions, there are several forecasting techniques that can be used. In fact, the accuracy of forecasting can be observed to obtain significant results in the projection of electricity consumption.5 In this study, three different exponential smoothing models were utilised to forecast electricity consumption: simple, Holt, and Brown’s exponential smoothing.\n\nThis aim of this research was to conduct a study in order to forecast electricity consumption in Malaysia until the year 2032. This research also attempts to identify the most appropriate exponential smoothing model in forecasting electricity consumption.\n\n\nLiterature review\n\nLee et al.,7 conducted a study involving six different forecasting methods, which were used to predict electricity consumption in Universiti Tun Hussein Onn Malaysia (UTHM), Malaysia. The study selected a mean absolute percentage error (MAPE) as the measurement of error. Historical data were obtained monthly from 2011 until 2017 which generated a projection up until December 2018. From the six forecasting models, Holt-Winters’ exponential smoothing was found to be the best technique implemented due to having the lowest MAPE. Similarly, Nazim and Afthanorhan8 also found that Holt’s exponential smoothing was the best method to predict Malaysia’s population from 2004 to 2020. The study selected a mean square error (MSE) as a criterion to determine the best model. There were four different techniques used which were single exponential smoothing (SES), double exponential smoothing (DES), Holt’s exponential smoothing, and adaptive response rate exponential smoothing (ARRES). Lima et al.,9 claimed that economic data could be forecasted using Holt-Winters’ exponential smoothing, which involves comparing additive and multiplicative practices. The results showed that multiplicative exhibited the best forecasting performance. Maçaira et al.,10 forecasted the best yearly projection for residential electricity consumption in Brazil by applying exponential smoothing. All the studies mentioned above provided economic projection values together with consumption growth and were validated by the accuracy of the forecast.\n\nIn contrast, Popeangă and Lungu11 found that the double moving average was the best technique in forecasting energy consumption in Romania from quarter one until quarter four of 2014. The study used two different moving average practices. Suresh12 used an autoregressive integrated moving average model (ARIMA) to analyse and forecast electricity consumption in India. The proposed ARIMA with the neural network (NN) model provided the best future time-series forecasting. A data set of 40 years of electricity consumption was analysed by Mahia et al.,13 using ARIMA methods. Several steps were conducted, and the best model was selected based on the lowest Akaike Information Criterion (AIC). Notably, the literature has specific reasons to conduct a moving average when the data set performs seasonally, particularly throughout the study period.\n\nFrom a business perspective, exponential smoothing is used in projecting sales. For example, Sidqi and Sumitra14 applied the single and double exponential smoothing in a study with MAPE as the criterion to determine the accuracy of the forecast model. As a result, the single exponential smoothing exhibited the lowest MAPE. In the agricultural sector, Talwar and Goyal15 analysed and compared coriander prices in India using several exponential smoothing methods. The results showed that the Holt-Winters’ trend adjusted model provided the best model with the lowest error measurement in MSE. A study by Booranawong and Booranawong16 in Thailand showed that the double exponential smoothing method provided better performance in predicting Thai chilli and lemongrass prices. The study utilised MAPE to determine the minimum error measurement from other methods such as multiplicative Holt-Winters’ (MHW) and additive Holt-Winters’ (AHW). The forecasted prices of the agricultural products were from October 2016 to December 2019. Regardless of the sector, exponential smoothing is very suitable to conduct forecasting together with the least error of measurement, such as MAPE.\n\nBased on previous literature, exponential smoothing has been widely used, and this technique captures the time series that may change its behaviour, and the model parameters should adapt to that change in behaviour as well.17 Currently, studies that provide exponential smoothing as a mechanism to predict the electricity consumption of the residential sector are limited. Therefore, this study selected this method as it is considered an appropriate technique to conduct a forecasting of the residential electricity consumption in Malaysia.\n\n\nMethods\n\nThree exponential smoothing models were used to forecast electricity consumption in this study: simple exponential smoothing, Holt’s exponential smoothing, and Brown’s exponential smoothing. Yearly data from 1997 to 2018 was obtained from the Malaysia Energy Information Hub (MEIH). The forecasting period started from the year 2019 until 2032. Details on the function and formula of the simple exponential smoothing, Holt’s exponential smoothing, and Brown’s exponential smoothing are explained in the following sections.\n\nSimple exponential smoothing is the most widely used model in forecasting if there are no cyclic variation patterns or consistent growing patterns involved.14 The formula for this method is as follows18:\n\nwhere:\n\nFt+m: simple exponentially forecast value in period m, for m=1,2,3,…t; yt: actual value in time t;\n\nα: unknown smoothing constant to be determined for value between 0 and 1;\n\nFt: forecast value at period t.\n\nHolt’s exponential smoothing can be used in forecasting when there is a linear trend in the historical data of the forecast. According to Alias,19 this method requires three equations which are exponential smoothed series, trend estimate, and forecast.\n\nExponential smoothed series:\n\nTrend estimate:\n\nForecast for m period:\n\nwhere:\n\nSt: exponential smoothed series;\n\nTt: trend estimates;\n\nFt+m: forecast for m-step-ahead period.\n\nThis method is also known as the double exponential smoothing and can be used if there is a linear trend in the data. The trend is a smoothed estimate of average growth at the end of each period.17 The formula for Brown’s exponential smoothing is as follows:\n\nSt: exponentially smoothed value of yt at time t;\n\nSt′: double exponentially smoothed value of yt at time t;\n\nat: computes the difference between the exponentially smoothed values;\n\nbt: computes the adjustment factor;\n\nFt+m: forecast for m-step-ahead period.\n\nAccording to Kalekar,17 the forecasting model should be validated. Here, an error measurement such as mean absolute percentage error (MAPE), relative mean square error (RMSE), or mean absolute error (MAE) is needed. The selection of an error measurement has a significant effect in determining the most accurate forecasting method. In this study, MAPE was selected to verify the model because it is the most suitable measurement to compare the accuracy of the forecasting methods, as it measures relative performance.7,14,20 A low MAPE score indicates that the forecasting model has a good performance.21 The range of the MAPE score is shown in Table 1.\n\n\nResults\n\nAn analysis of the historical data was conducted to examine the pattern of electricity consumption trend (kilotonne of oil equivalent, ktoe) from 1997 until 2018 for the residential sector in Malaysia.\n\nBased on Figure 1, the trend pattern in this time series is linear and no seasonality is involved. In addition, the graph shows a constant increase in the pattern. In 2016, a total of 2679 ktoe of electricity was consumed as the highest value. The consumption value gradually decreased from 2017 to 2018 with values of 2610 ktoe and 2553 ktoe respectively as shown in Table 2. Thus, all three exponential smoothing methods, namely simple, Holt’s and Brown exponential smoothing were capable of forecasting electricity consumption. The lowest MAPE was compared to identify the most appropriate exponential smoothing model.\n\n(Source: Malaysia Energy Information Hub, https://meih.st.gov.my/statistics.)\n\nThe simple exponential smoothing was analysed using SPSS version 26 (IBM SPSS Statistics, RRID:SCR_019096) starting from the year 2019. Referring to Figure 2, the three lines represent the limit of the forecast values for the forecast year: yellow indicates the upper limit of electricity consumption, purple indicates the best prediction of electricity consumption, and brown indicates the lower limit of electricity consumption at a particular year. This means that the expected electricity consumption could fall between the green and brown dotted lines.\n\nUCL: upper confidence level (upper limit); LCL: lower confidence level (lower limit).\n\nBased on Table 3, the year 2019 recorded the best forecasted electricity consumption, which is 2553 ktoe; the consumption maintains this value until 2032. However, this method also predicted a wide range of possible values until 2032. For example, the electricity consumption in 2032 is predicted to be between 3345 ktoe as the upper limit and 1760 ktoe as the lower limit, but the best value generated is 2553 ktoe.\n\nThe accuracy of the forecasting value was measured via model fit statistics. As shown in Table 4, there are three error measurement scores generated by SPSS version 26: relative mean square error (RMSE), mean absolute percentage error (MAPE), and mean absolute error (MAE). For simple exponential MAPE, the score is 5.678.\n\nFigure 3 shows Holt’s exponential smoothing method, which was conducted. It is expected that the electricity consumption value would fall between the pink and brown dotted lines for the forecast year, but the width is narrower compared to the previous method. It can be observed that the forecast has a considerable upward trend from 2019 until 2032.\n\nUCL: upper confidence level (upper limit); LCL lower confidence level (lower limit).\n\nThe value of the best forecasted electricity consumption was 2647 ktoe for 2019 and 3873 ktoe for 2032 as shown in Table 5. In 2032, the predicted electricity consumption value would be between 3360 and 4386 ktoe whereas the best projected value is 3873 ktoe. Table 6 shows the accuracy of the forecasting where the score measured by MAPE is 2.299.\n\nThe last forecasting method is Brown’s exponential smoothing (Figure 4). This method enjoys a very wide range of forecasting values where the upper and lower limit values experienced a steep trend. In 2019, the forecasted electricity consumption value is 2402 ktoe. However, the value gradually decreases year by year until 2032 with a consumption value of 2399 ktoe as presented in Table 7. In 2032, the predicted electricity consumption value would be within 4967 ktoe as the maximum value and 90 ktoe as the minimum value; the best projected value is 2399 ktoe. Table 8 shows the MAPE score for Brown’s exponential smoothing, which is 3.125. The lower the MAPE score, the higher the accuracy of the forecast.\n\nUCL: upper confidence level (upper limit); LCL: lower confidence level (lower limit).\n\n\nDiscussion\n\nTable 9 shows the summary of all smoothing methods using MAPE as the measurement. Holt’s exponential smoothing is the most suitable method to predict the electricity consumption of the residential sector in Malaysia. This is because this method has the lowest MAPE score which is 2.299 compared to the other two methods. The result is consistent with Omer et al.22 where they used MAPE to identify the most appropriate prediction model. Therefore, in this study, Holt’s exponential smoothing is the best method to forecast future electricity consumption in Malaysia.\n\nTable 5 lists the forecasting values from 2019 until 2032 generated by Holt’s exponential smoothing. In 2032, the maximum electricity consumption is 4386 ktoe and the minimum consumption is 3360 ktoe. However, the best predicted value is 3873 ktoe.\n\n\nConclusion\n\nThe aim of the study was to forecast the total electricity consumption in Malaysia until the year 2032 and to identify the most appropriate exponential smoothing model to predict this consumption. Based on the results and discussion, Holt’s exponential smoothing was found to be the most appropriate model in forecasting electricity consumption in Malaysia. Generally, electricity consumption in residential sectors comes from electrical appliances. Hence, based on the predicted consumption growth, energy efficiency regulations by electrical manufacturers should be revised. Campaigns for less energy demand in households should also be implemented. This can benefit both parties by maximising energy efficiency and minimising electricity consumption. As a suggestion for further study, moving average methods can also be applied to predict electricity consumption. There are various types of moving average method including the integrated model such as autoregressive–moving-average (ARMA), autoregressive integrated moving average (ARIMA), autoregressive integrated moving average- neural network (ARIMA-NN), or the hybrid model. These methods can be used by future researchers to further expand on this study.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgments\n\nThis study was funded by TNB Seed Fund 2020 (U-TR-RD-20-01). We would like to thank UNITEN R&D for the financial support of this project entitled Domestic Electricity Demand Model for TNB Regulation Strategy.\n\n\nReferences\n\nBekhet HA, Othman NS: The role of renewable energy to validate dynamic interaction between CO2 emissions and GDP toward sustainable development in Malaysia. Energy Econ. 2018; 72: 47–61. Publisher Full Text\n\nBekhet HA, Harun NH: Determining the dynamic linkages between renewable electricity generation and its determinants toward sustainable energy in Malaysia. World Review of Science, Technology and Sustainable Development. 2018; 14(4): 295–329. Publisher Full Text\n\nChandran VGR, Sharma S, Madhavan K: Electricity consumption–growth nexus: the case of Malaysia. Energy Policy. 2010; 38(1): 606–612. Publisher Full Text\n\nPusat Tenaga Malaysia: National Energy Balance 2004 Malaysia. Selangor: Pusat Tenaga Malaysia; 2004.\n\nNguyen VH, Vo CV, Nguyen KT, et al.: Forecast on 2030 Vietnam electricity consumption. Engineering, Technology & Applied Science Research. 2018; 8(3): 2869–2874. Publisher Full Text\n\nOzoh P, Abd-Rahman S, Labadin J, et al.: A comparative analysis of techniques for forecasting electricity consumption. Int. J. Comput. Appl. 2014; 88(15): 8–12. Publisher Full Text\n\nLee YW, Tay KG, Choy YY: Forecasting electricity consumption using time series model. Int. J. Eng. Technol. 2018; 7(4): 218–223. Publisher Full Text\n\nNazim A, Afthanorhan A: A comparison between single exponential smoothing (SES), double exponential smoothing (DES), holt’s (brown) and adaptive response rate exponential smoothing (ARRES) techniques in forecasting Malaysia population. Glob. J. Math. Anal. 2014; 2(4): 276–280. Publisher Full Text\n\nLima S, Gonçalves AM, Costa M: Time series forecasting using Holt-Winters exponential smoothing: An application to economic data. AIP Conference Proceedings. AIP Publishing LLC; 2019, December; Vol. 2186(No. 1): p. 090003.\n\nMaçaira PM, Souza RC, Oliveira FC: Modelling and forecasting the residential electricity consumption in Brazil with pegels exponential smoothing techniques. Procedia Comput. Sci. 2015; 55: 328–335. World energy markets observatory (WEMO). A strategic overview of the global energy markets. 2017,”2017.\n\nPopeangă J, Lungu I: Forecasting Final Energy Consumption using the Centered Moving Average Method and Time Series Analysis. Database Syst. J. 2014; 5(1): 42–50.\n\nSuresh M: Analyzing and Forecasting of Electricity Consumption by Integration of Autoregressive Integrated Moving Average Model with Neural Network on Smart Meter Data. Turk. J. Comput. Math. Educ. 2021; 12(11): 1986–1997. Publisher Full Text\n\nMahia F, Dey AR, Masud MA, Mahmud MS: Forecasting electricity consumption using ARIMA model. 2019 International Conference on Sustainable Technologies for Industry 4.0 (STI). IEEE; 2019, December; pp. 1–6.\n\nSidqi F, Sumitra ID: Forecasting product selling using single exponential smoothing and double exponential smoothing methods. IOP Conference Series: Materials Science and Engineering. IOP Publishing; 2019, November; Vol. 662(No. 3): p. 032031.\n\nTalwar A, Goyal CK: A comparative study of various exponential smoothing models for forecasting coriander price in Indian commodity market. International Bulletin of Management and Economics Volume 2019.\n\nBooranawong T, Booranawong A: Double exponential smoothing and Holt-Winters methods with optimal initial values and weighting factors for forecasting lime, Thai chili and lemongrass prices in Thailand. Eng. Appl. Sci. Res. 2018; 45(1): 32–38.\n\nKalekar PS: Time series forecasting using holt-winters exponential smoothing. Kanwal Rekhi school of information Technology. 2004; 4329008(13): 1–13.\n\nMuniroh MF, Ismail N, Lazim MA: Combination of forecasts with an application to unemployment rate. Pertanika J. Sci. Technol. 2017.\n\nLazim A: Introductory business forecasting: A practical approach. 3rd ed.University Publication Centre (UPENA), UiTM 2005, 2007, 2011 . 2011.\n\nLewis CD: Industrial and Business Forecasting Methods. London: Butterworths; 1982.\n\nChang PC, Wang YW, Liu CH: The development of a weighted evolving fuzzy neural network for PCB sales forecasting. Expert Syst. Appl. 2007; 32(1): 86–96. Publisher Full Text\n\nOmer A, Blbas H, Kadir D: A Comparison between Brown’s and Holt’s Double Exponential Smoothing for Forecasting Applied Generation Electrical Energies in Kurdistan Region. Cihan Univ.-Erbil Sci. J. 2021; 5(2): 56–63. Publisher Full Text"
}
|
[
{
"id": "143421",
"date": "27 Jul 2022",
"name": "Azer Dilanchiev",
"expertise": [
"Reviewer Expertise ReneRenewable energy",
"poverty",
"regional 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\nTo begin with, it was a pleasure for me to review this engaging paper. In my perspective, the paper is valid. Throughout the investigation, the authors created a well-written, well-structured manuscript while adhering to rigorous research procedures. I'd like to encourage the authors to apply the following tips to revise and improve their writing:\nThe introduction gave useful information on the desired topic, but it needs to be changed to be relevant. There are several gaps in the introduction. The introduction section, in particular, failed to clarify the earlier research contribution, limits, and novelty of this study to the literature and practice. It is also suggested that a paragraph at the end of this section explain the study structure. It is recommended to enlarge the introduction part in general.\n\nThe authors should use a consistent referencing style throughout the manuscript. The literature review has to be reviewed and rebuilt once more. Cite current and relevant references from well-reputed journals. I am the coauthor of the first and second papers listed below. The first paper considers the case of Pakistan the role of Technological Innovations: A Pathway for Addressing Energy Sustainability which can be incorporated and compared with the case of Malaysia's electricity consumption. While the second paper deals with the case of China, again the role of renewable energy is highlighted. I thinks taking into account these two paperss the authors can compare the case of Malaysias and the cases of China and Pakistan, in relation to the issue of energy sustainability and renewable energy.\nhttps://www.frontiersin.org/articles/10.3389/fenvs.2022.888080/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICL -https://doi.org/10.3389/fenvs.2022.888081\nhttps://www.sciencedirect.com/science/article/abs/pii/S096014812200628 -https://doi.org/10.1016/j.renene.2022.04.162\nhttps://www.sciencedirect.com/science/article/abs/pii/S036054422201659 - https://doi.org/10.1016/j.energy.2022.1247563\n\nThe methodology is OK but cite the most relevant and current references. The methodology of the article is clear and justified by the literature. Better to cite the latest and relevant studies on similar topics.\n\nThe discussion part is very small, It needs to be enlarged.\n\nThe robustness of the empirical investigation is missing; please include it.\n\nIn conclusion, indicate whether your findings follow or oppose the previous works.\n\nPlease indicate in conclusion policy recommendations, limitations and recommendations for future work.\n\nGenerally, the paper needs major revision and professional English editing. However, some tables and graphs can be transferred to the appendix. In addition, the paper needs to be enlarged.\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
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https://f1000research.com/articles/11-54
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https://f1000research.com/articles/9-692/v1
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09 Jul 20
|
{
"type": "Data Note",
"title": "Supplementary data on virus-like particles in the brainstem of Parkinson’s disease patients and controls",
"authors": [
"Robert R. Dourmashkin",
"Peter Locker",
"Sherman A. McCall",
"Matthew J. Hannah",
"Peter Locker",
"Sherman A. McCall",
"Matthew J. Hannah"
],
"abstract": "In this study, we present 84 transmission electron microscopy (TEM) images of human brainstem tissue from 11 cases of late onset Parkinson’s disease (PD). The tissues were fixed, embedded, sectioned, and stained for TEM application. In addition, we present 14 images from autopsy specimens of 1 case of human poliomyelitis infection as positive controls and 14 images from 8 cases of autopsy specimens of other conditions as negative controls. In the TEM images of the PD cases there were cytoplasmic inclusion bodies consisting of virus-like particles (VLP) 30 nm in diameter that were associated with endoplasmic reticulum membranes. In the nuclei of the PD neurons there were VLP ranging from 40 nm to 50 nm in diameter. In the poliomyelitis cases, similar particles as were observed in PD which were interpreted to be poliomyelitis virus particles. In the negative controls one case was identified which showed similar VLP (Figure 1, controls). A Lewy body was found in this “control” case (Figure 10) suggesting that this was an undiagnosed case of PD. Cytoplasmic ribosomes measuring approximately 17 nm were observed in the control neurons.",
"keywords": [
"Virus-like particles",
"Parkinson’s disease",
"transmission electron microscope imaging"
],
"content": "Introduction\n\nIn our previous communication, we presented a number of TEM images selected from our work on PD. We also presented our immunohistochemical results in which we detected enterovirus antigen in PD brainstem tissue1. In order to assist in the interpretation of our TEM results, we now present a larger number of TEM images from PD archives together with relevant controls. We also include TEM images of Lewy bodies from the cases of PD, the diagnostic sign of PD (see Underlying data)2.\n\n\nMethods\n\nThe methods for TEM were the same as those employed in our previous communication1. Included were 8 control cases, 1 case of poliomyelitis and 11 cases of Parkinson’s disease. The tissue samples from the control cases were obtained from the John Radcliffe Hospital, Department of Neuropathology. The tissue samples from the PD cases and from the poliomyelitis case were from the Armed Forces Institute of Pathology, in Washington DC, now closed.\n\nControls: Case 06/126: 87 y. o. female, no cause of death known; Case 06/110: 70 y. o. male, prostate cancer; Case 06/112: 87 y. o. male, perforated gastric ulcer; Case 05/66: 26 y. o. female, cystic fibrosis; Case 05/152: 51 y. o. female, stomach cancer. All PD cases died of PD. The polio case was a 32 y. o. male that died of poliomyelitis.\n\nStudy of brain specimens had been cleared for ethical agreement by the National Ethics Committee for Oxford UK, rec. no. 07/H0606/85. The brain samples from human autopsy material were obtained from the pathology collections of the John Radcliffe Hospital, Oxford UK and the former Armed Forces Institute of Pathology, Washington DC USA. These institutions approved the use of the tissues for research and they were satisfied that no further ethical approval was required. In the case of the material from the UK, the principal author releases the “tissue disclaimer” from the Thomas Willis Oxford collection, at the Neuropathology Department.\n\n\nConclusions\n\nWe note the role α-synuclein plays in the pathogenesis of PD3. It is conceivable that a virus is involved with α -synuclein in the pathogenesis of PD.\n\n\nData availability\n\nFigshare: Supplementary data on virus-like particles in the brainstem of Parkinson’s disease patients and controls. https://doi.org/10.6084/m9.figshare.12326489.v12.\n\nThis project contains the following underlying data:\n\nLegends for TEM images of PD brain.\n\nParkinson’s Figure 1. Low magnification of a PD neuron, original image 2.13b015. Cytoplasmic inclusion bodies are shown (arrows).\n\nParkinson’s Figure 2. Low magnification of a PD neuron of the same case, image 2.13b025. Cytoplasmic inclusion bodies are shown (arrows).\n\nParkinson’s Figure 3. High magnification of a cytoplasmic neuron of the same case, image 2.13b028. Multiple VLP are shown.\n\nParkinson’s Figure 4. Low magnification of a PD neuron of the same case, image 2.13b032 Cytoplasmic inclusion bodies (arrow) and external inclusion bodies are shown.\n\nParkinson’s Figure 5. High magnification of a cytoplasmic inclusion body in a PD neuron in the same case, image 2.13b031. Many VLP are shown.\n\nParkinson’s Figure 6. High magnification of a cytoplasmic inclusion body in a PD neuron in the same case, image 2. 13b033. Many VLP are shown.\n\nParkinson’s Figure 7. High magnification of a cytoplasmic inclusion body in a PD neuron in the same case as above, image 2.13b046. There are proliferating cytoplasmic membranes and VLP associated with membranes.\n\nParkinson’s Figure 8. Low magnfication of a PD neuron in the same case. Inclusion body is shown (arrow). Image 2.13b055.\n\nParkinson’s Figure 9. High magnification of an inclusion body in the PD neuron in the same case, image 2.13b060. Many VLP are shown.\n\nParkinson’s Figure 10. Low magnification of a neuron in the same case, image 2.13b072. Cytoplasmic inclusion bodies are shown (arrow).\n\nParkinson’s Figure 11. Image of a Lewy body in the same case, image 2.13c012.\n\nParkinson’s Figure 12. Low magnification of a PD neuron in the same case, image 2.13013. Cytoplasmic inclusion body is indicated (arrow).\n\nParkinson’s Figure 13. Image of a cytoplasmic inclusion body showing proliferation of cytoplasmic membranes and VLP. Image 2.13c017.\n\nParkinson’s Figure 14. Measurements of intranuclear VLP in a PD neuron. NM=nuclear membrane. Image 2.13004.\n\nParkinson’s Figure 15. Low magnification of a PD neuron. Cytoplasmic inclusion bodies are indicated (arrows). Image 2.13028.\n\nParkinson’s Figure 16. In the nucleus of a PD neuron, intranuclear VLP are indicated (arrows), image 2.13026.\n\nParkinson’s Figure 17. The same image as Fig. 16, with measurements of VLP. Image 2.13027.\n\nParkinson’s Figure 18. In another PD case, low magnification image of damaged neuroglia. Image 3.00800.\n\nParkinson’s Figure 19. In the same PD case, a Lewy body. Image 03.08049.\n\nParkinson’s Figure 20. In the same PD case, a neuron showing a cytoplasmic inclusion body. Image 3.02001 (arrow)\n\nParkinson’s Figure 21. At higher magnification, an image of the same inclusion body shown in Fig.29, consisting of VLP. Image 3.02002.\n\nParkinson’s Figure 22. In the same PD case, an image of a neuron with multiple VLP close to the internal face of the nuclear membrane (arrow). Image 3.13007.\n\nParkinson’s Figure 23. In the same PD case, two VLP are shown budding from the internal face of a nucleus (arrows.) Image 3.13016.\n\nParkinson’s Figure 24. In the same PD case, a high magnification image shows multiple VLP arranged on an endoplasmic membrane in a cytoplasmic inclusion body. Image 3i.13.09006.\n\nParkinson’s Figure 25. In the same PD case, measurements of intranuclear VLP. Image 3i.13.09021.\n\nParkinson’s Figure 26. In another PD case, at high magnification, an image of multiple VLP in a cytoplasmic inclusion body. Image 4.08b003.\n\nParkinson’s Figure 27. In the same PD case as above, an image of VLP replicating on endoplasmic membranes. N = nucleus, C = cytoplasm. Image 4. 08b006.\n\nParkinson’s Figure 28. In the same case, a low magnification image of a PD neuron showing cytoplasmic inclusion bodies (arrows). Image 4.08b009.\n\nParkinson’s Figure 29. In the same case, a low magnification image of a PD neuron showing cytoplasmic inclusion bodies (arrows). Image 4.08b014\n\nParkinson’s Figure 30. In the same case, a high magnification image, measurements of intranuclear VLP. Image 4.08b016.\n\nParkinson’s Figure 31. In the same case, intranuclear VLP are shown (arrows). Image 4.08b021.\n\nParkinson’s Figure 32. In the same case, intranuclear VLP are shown (arrows). Image 4.08b022.\n\nParkinson’s Figure 33. In the same case, intranuclear VLP are shown (arrow). Image 4.08b030.\n\nParkinson’s Figure 34. The same area as illustrated in Fig. 43. Measurements are shown. Image 4.08b032.\n\nParkinson’s Figure 35. In the same case, a low magnification image of the same PD case shows multiple cytoplasmic inclusion bodies. Image 4.08b036.(arrows)\n\nParkinson’s Figure 36. In another PD case, a high magnification image of intranuclear VLP emerging from virus matrix. Image 4.08001.\n\nParkinson’s Figure 37. Another image of the same area as Fig.37, in the proximity of the nucleolus. Image 4.08003\n\nParkinson’s Figure 38. Another image of the same area as Fig. 37. Image 4.08005.\n\nParkinson’s Figure 39. Another PD case. Intranuclear VLP situated close to the nuclear membrane (arrow). Image 4.08009.\n\nParkinson’s Figure 40. Another PD case. A cytoplasmic inclusion body. Image 4.08015.(Arrow)\n\nParkinson’s Figure 41. The same PD case as Fig. 43. Intranuclear VLP (arrows). Image 4.08017.\n\nParkinson’s Figure 42. Parkinson’s disease cases, neurons of the basal ganglia. Image of a Lewy body. Image 5b.08001.\n\nParkinson’s Figure 43. Clusters of VLP in a cytoplasmic inclusion body. Image 5D.08002.\n\nParkinson’s Figure 44. Large intranuclear VLP. Image 5D.08004.\n\nParkinson’s Figure 45. Same image, with measurements. Image 5D.08005.\n\nParkinson’s Figure 46. Same PD case. Large intranuclear VLP close to and adhering to the internal face of the nuclear membrane. (arrows). Image 5D.08006.\n\nParkinson’s Figure 47. Same PD case. Similar VLP adhering to the internal face of the nuclear membrane. Image 5D08007.\n\nParkinson’s Figure 48. Same PD case. Measurements of VLP in a cytoplasmic inclusion body. Image 5D.08018.\n\nParkinson’s Figure 49. Same PD case. Measurements of VLP in a cytoplasmic inclusion body. Image 5D.08028.\n\nParkinson’s Figure 50. Same PD case. Arrows indicating membranes in a cytoplasmic inclusion body. Image 5D08017.\n\nParkinson’s Figure 51. Another PD case. Intranuclear polyribosomes. Image 6.08002.\n\nParkinson’s Figure 52. Higher magnification of similar image, with measurements. Image 6.08004.\n\nParkinson’s Figure 53. In the same PD case, a Lewy body. Image 6.08011.\n\nParkinson’s Figure 54. High magnification of a Lewy body. Image 6.08013.\n\nParkinson’s Figure 55. Low power of neuron from another PD case, with cytoplasmic inclusion bodies (arrows). Image 7.08b001.\n\nParkinson’s Figure 56. Low magnification of a cell from the same PD case with a Lewy body Image 7.08019.\n\nParkinson’s Figure 57. Low magnification of neuron from another PD case, with cytoplasmic inclusion bodies (arrow). Image 8.08001.\n\nParkinson’s Figure 58. Same case, high magnification of neuron with large intranuclear VLP (arrows). Image 8.08008. N=Nucleus.\n\nParkinson’s Figure 59. Same area of nucleus, (arrows). Image 8.08009.\n\nParkinson’s Figure 60. Same PD case, large intranuclear VLP. Image 8.08025.\n\nParkinson’s Figure 61. Same PD cell, large intranuclear VLP, measurements of VLP. (arrows). Image 8.08027.\n\nParkinson’s Figure 62. Same PD case, low magnification of a neuron with cytoplasmic inclusion bodies (arrows). Image 8.08034.\n\nParkinson’s Figure 63. Same PD case, budding intranuclear VLP. Image 8.08036.\n\nParkinson’s Figure 64. Same PD case, intranuclear VLP budding from the internal leaf of the nuclear membrane. Measurements, 8.08040.\n\nParkinson’s Figure 65. Same PD case, intranuclear VLP. Measurements, image 8.08049.\n\nParkinson’s Figure 66. Another PD case. Cytoplasmic VLP. Image 9.08016.\n\nParkinson’s Figure 67. Same case. Cytoplasmic VLP. Image 9.08021.\n\nParkinson’s Figure 68. Same case. Cytoplasmic VLP. Image 9.08026.\n\nParkinson’s Figure 69. A PD case. Intranuclear VLP budding from internal nuclear membrane of neuron. Image 10.08a001.\n\nParkinson’s Figure 70. Same PD neuron, measurements. Image 10.08a005.\n\nParkinson’s Figure 71. Same PD case, a capillary and surrounding endothelium, the latter showing apoptosis. Low magnification. Image 10.08a006.\n\nParkinson’s Figure 72. Same PD endothelial cell. High magnification showing large numbers of clustered small VLP. Image 10.08a008.\n\nParkinson’s Figure 73. Same PD endothelial cell, high magnification. Large numbers o0f small VLP. Image 10.08a019.\n\nParkinson’s Figure 74. A PD case, showing large VLP in the cytoplasm and measurements. Image 13.09c006.\n\nParkinson’s Figure 75. A PD case. A Lewy body is shown in the cytoplasm of s neuron. Image 13.09c010.\n\nParkinson’s Figure 76. A PD case. A Lewy body free in the neuropil. Image 13.09019.\n\nParkinson’s Figure 77. A PD case. Large VLP in the nucleus and cytoplasm of a neuron. Image 13a09009. (arrows).\n\nParkinson’s Figure 78. Another PD case. A Lewy body free in the neuropil. Image 14.09b006.\n\nParkinson’s Figure 79. Same PD case. Small intranuclear VLP clustered in groups. Image 14.09c035. (N=nucleolus).\n\nParkinson’s Figure 80. Same PD case. Small intranuclear VLP, clustered in groups. Image 14.09c045.\n\nParkinson’s Figure 81. Same PD case. Large intranuclear VLP budding from membranes. Image 14.431037.\n\nParkinson’s Figure 82. Another PD case. Large intranclear VLP (arrow). Image 16.09c001.\n\nParkinson’s Figure 83. Higher magnification of same area. Image 16.09c005.\n\nParkinson’s Figure 84. In the same PD case, large intranuclear VLP. Image 16.09c014.\n\nLegends of TEM images of poliomyelitis spinal cord.\n\nPoliomyelitis Figure 1. A case of human poliomyelitis. Large numbers of small virus particles embedded in a matrix, at the periphery of a neuron. Image 5a.13021.\n\nPoliomyelitis Figure 2. Same polio case. Clusters of small virus particles in an inclusion body. Image 5a.13022.\n\nPoliomyelitis Figure 3. Same polio case, low magnification. Neuron in apoptosis. Virus inclusion body (arrow). Image 5a.13025.\n\nPoliomyelitis Figure 4. Same polio case. Intranuclear virus particles (arrow). Image 5a.13026.\n\nPoliomyelitis Figure 5. Same image as Fig. 4, measurements of virus particles. Image 5a.13027.\n\nPoliomyelitis Figure 6. High magnification of a polio inclusion body, showing clusters of virus particles, both free and associated with endoplasmic membranes. Image 5a.13029.\n\nPoliomyelitis Figure 7. Case of human poliomyelitis. Clusters of virus particles, embedded in amorphous matrix. Image 48.05006.\n\nPoliomyelitis Figure 8. Case of human poliomyelitis. Cytoplasmic virus particles. Image II.48.05001.\n\nPoliomyelitis Figure 9. Case of human poliomyelitis. Image II.48.05002 Low magnification. (arrow)\n\nPoliomyelitis Figure 10. Case of human poliomyelitis. Low magnification. Image II48.05003. Inclusion body shown. (arrow)\n\nPoliomyelitis Figure 11. Case of human poliomyelitis. Virus particles embedded in amorphous matrix, associated with cytoplasmic membranes. Image II.48.05005.\n\nLegends of TEM images of control brain.\n\nControl Figure 1. Ribosomes in Nissl body, and mitochondrion. Measurements, Image 9.090117.\n\nControl Figure 2. Control case. Ribosomes in a Nissl body. Measurements, image 9.08039.\n\nControl Figure 3. Control case. Nissl body. Image 10.09b004.\n\nControl Figure 4. Control case. Nerve fibre. High magnification, image 10.09001.\n\nControl Figure 5. Same area as in Fig. 97, Nissl body. Low magnification, image 10.09004.\n\nControl Figure 6. Control case; a group of ribosomes in a neuron in the basal ganglia. Measurements, image 10.09015.\n\nControl Figure 7. Control case; a group of ribosomes in a Nissl body in the same area as above. Image 10a09009.\n\nControl Figure 8. Measurements. Control case, as above; endoplasmic reticulum in the cytoplasm of a neuron. Image 10c.09011.\n\nControl Figure 9. A case that was reported as being a control case. VLP characteristic of PD are shown (arrows). Image 11.09b001.\n\nControl Figure 10. In a same case as in Fig. 9, an intracellular Lewy body. Image 11.09006.\n\nControl Figure 11. A control case, showing cytoplasm and nucleus. Image 12.09015.\n\nControl Figure 12. Control case. Image 1209b004.\n\nControl Figure 13. Control case. Image 1209b015.\n\nControl Figure 14. Control ribosomes, measurements. Image x10.09011.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Author contributions\n\n\n\nRobert Dourmashkin: Preparation of tissue for TEM; carrying out TEM; Interpretation of TEM images; writing this article.\n\nPeter Locker: Management of digital images.\n\nSherman McCall: Selecting and submitting pathological specimens to the authors from the AFIP tissue bank for this study.\n\nMatthew Hannah: Management of TEM.\n\n\nAcknowledgements\n\nProf. Margaret M. Esiri, Department of Clinical Neurology, University of Oxford, UK; Department of Neuropathology, Oxford Radcliffe NHS Trust, UK (retired). Acknowledgements are offered to Prof. Esiri for the work she did in selecting pathological specimens from the Department tissue bank and advice concerning the interpretation of the RRD images.\n\nMrs. S. Dourmashkin: Encouragement for RRD’s work.\n\n\nReferences\n\nDourmashkin RR, McCall SA, Dourmashkin N, et al.: Virus-like particles and enterovirus antigen found in the brainstem neurons of Parkinson’s disease [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Res. 2018; 7: 302. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDourmashkin R, Locker P, McCall SA, et al.: Supplementary data on virus-like particles in the brainstem of Parkinson’s disease patients and controls. f1000research.com. 2020. Dataset. http://www.doi.org/10.6084/m9.figshare.12326489.v1\n\nKim S, Kwon SH, Kam TI, et al.: Transneural propagation of pathologic α-synuclein from the gut to the brain models of Parkinson’s disease. Neuron. 2019; 103(4): 627–641.e7. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "66787",
"date": "20 Aug 2020",
"name": "Doris Bucher",
"expertise": [
"Reviewer Expertise Virology"
],
"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\nR.R. Dourmashkin and colleagues provide additional TEM images from their work on Parkinson’s Disease (PD). Earlier this group detected enterovirus antigen in PD brainstem tissue. Dourmashkin et al. show additional TEM of virus-like particles 30 nm diameter (VLPs) associated with endoplasmic reticulum membranes from PD cases. In nuclei of neurons from PD cases VLPs of 40-50 nm diameter were found. Similar particles were also found in polio cases. Lewy bodies were also found. Cytoplasmic ribosomes of 17 nm were observed in control neurons. It is valuable to the scientific community and PD researchers to have access to this supplemental material.\n\nOverall, need to improve labelling of figure legends by use of arrows pointing to key features.\nPD Brain:\nFig. 1-4\n\nFig. 5 use arrow to i.d. VLPs assoc. with cytoplasmic inclusion body.\n\nFig. 7., Fig. 8, Fig. 9—need arrows.\n\nFig. 13—need arrow.\n\nFig. 14 –NM not labelled.\n\nFig. 16—VLP no arrows.\n\nFig. 31, 32 –need arrows.\n\nFig. 37-- same area as Fig. 36.\n\nFig. 51—need arrows.\n\nFig. 63—need arrows.\n\nFig. 66, Fig. 67. Fig. 68—difficult to see cytoplasmic membrane—need arrows.\n\nFig. 72, 73—need arrows.\n\nFig. 77—need arrows.\n\nFig. 79, 80, 81—need arrows.\n\nFig. 84—need arrows.\n\nPoliomyelitis Spinal Cord:—figures are out of order….\nFig. 1, Fig. 2—need arrows.\n\nFig. 6, 7, 8—need arrows.\n\nFig. 11—need arrows.\n\nControl Brain (Ribosomes, etc.):\nFig. 1—need arrows.\n\nFig. 7,8,9,10,11—need arrows.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
},
{
"id": "78179",
"date": "22 Feb 2021",
"name": "Marie-Eve Tremblay",
"expertise": [
"Reviewer Expertise brain ultrastructure",
"microglia",
"neurons",
"synapses",
"animal models",
"human post-mortem samples",
"stress",
"aging",
"neurodegenerative 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\nThis supplemental material provides additional transmission electron microscopy pictures in support of the presence of viral-like particles in the brain stem of post-mortem Parkinson's patient samples (compared with controls).\n\nThe rationale for providing additional pictures should be explained a little further, considering that these additional pictures do not provide more support to the original evidence published by the authors. In particular, it would have been useful to perform immunostaining or use additional validation methods to confirm that some of the viral-like particles are indeed viral-like particles and not something else (e.g. glycogen granules, which have a similar size and can also associate with the endoplasmic reticulum).\n\nIf presented as supplemental material, the pictures should have more annotations (e.g. arrows, pseudo-colours, etc.) to help readers visualize the structures of relevance. I would also recommend removing pictures showing glial processes, myelin, neurons (of note, sometimes neurons looked like astrocytes, it would be important to verify the ultrastructural identification criteria for the dataset), focusing on the topic of investigation: the viral-like particles.\nIn addition, the ultrastructural preservation of the samples is generally suboptimal, which could be accounted for by the most-mortem interval or the pH of the cerebrospinal fluid, known to affect brain ultrastructure. More information regarding the samples could be useful to help interpret the dataset.\n\nIs the rationale for creating the dataset(s) clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/9-692
|
https://f1000research.com/articles/10-846/v1
|
24 Aug 21
|
{
"type": "Research Article",
"title": "Association of smoking status with hospitalisation for COVID-19 compared with other respiratory viruses a year previous: a case-control study at a single UK National Health Service trust",
"authors": [
"David Simons",
"Olga Perski",
"Lion Shahab",
"Jamie Brown",
"Robin Bailey",
"David Simons",
"Lion Shahab",
"Jamie Brown",
"Robin Bailey"
],
"abstract": "Background: It is unclear whether smoking increases the risk of COVID-19 hospitalisation. We first examined the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections a year previous. Second, we examined the concordance between smoking status recorded on the electronic health record (EHR) and the contemporaneous medical notes. Methods: This case-control study enrolled adult patients (446 cases and 211 controls) at a single National Health Service trust in London, UK. The outcome variable was type of hospitalisation (COVID-19 vs. another respiratory virus a year previous). The exposure variable was smoking status (never/former/current smoker). Logistic regression analyses adjusted for age, sex, socioeconomic position and comorbidities were performed. The study protocol and analyses were pre-registered in April 2020 on the Open Science Framework. Results: Current smokers had lower odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (ORadj=0.55, 95% CI=0.31-0.96, p=.04). There was no significant association among former smokers (ORadj=1.08, 95% CI=0.72-1.65, p=.70). Smoking status recorded on the EHR (compared with the contemporaneous medical notes) was incorrectly recorded for 168 (79.6%) controls (χ2(3)=256.5, p=<0.001) and 60 cases (13.5%) (χ2(3)=34.2, p=<0.001). Conclusions: In a single UK hospital trust, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous, although it is unclear whether this association is causal. Targeted post-discharge recording of smoking status may account for the greater EHR-medical notes concordance observed in cases compared with controls.",
"keywords": [
"tobacco",
"smoking",
"respiratory infections",
"COVID-19",
"case-control study",
"hospitalisation"
],
"content": "Introduction\n\nCOVID-19 is a respiratory disease caused by the SARS-CoV-2 virus. There are in excess of 118 million confirmed COVID-19 cases globally, with over 2.6 million deaths reported (Johns Hopkins Coronavirus Resource Center, 2021). Large age and sex differences in case severity and mortality have been observed (Guan et al., 2020), with hypertension, diabetes and obesity identified as important risk factors (Fang et al., 2020). There are a priori reasons to believe that current smokers are at increased risk of contracting COVID-19 and experiencing greater disease severity once infected. SARS-CoV-2 enters epithelial cells through the ACE-2 receptor (Hoffmann et al., 2020). Evidence suggests that gene expression and subsequent ACE-2 receptor levels are elevated in the airway and oral epithelium of current smokers (Brake et al., 2020; Cai, 2020), potentially making smokers vulnerable to contracting SARS-CoV-2. Other studies, however, show that smoking downregulates the ACE-2 receptor (Oakes et al., 2018). In addition, smoking involves repeated hand-to-mouth movements, which may mean that smokers are more likely to contract respiratory viruses such as SARS-CoV-2 (Simons et al., 2020). Early data from the ongoing pandemic have not provided clear evidence for an association of smoking status with COVID-19 outcomes, with a living review and unadjusted Bayesian meta-analysis of over 60 studies indicating that current smokers, compared with those who had never smoked, may be at reduced risk of SARS-CoV-2 infection, while former smokers are at increased risk of hospitalisation, disease severity and in-hospital mortality compared with those who had never smoked (Simons et al., 2021).\n\nMost studies to date have been limited by the lack of appropriate controls, poor recording of smoking status and insufficient adjustment for relevant covariates. Many studies relied on routine electronic health records (EHRs) to obtain data on demographic characteristics, comorbidities and smoking status. This is problematic, as previous research suggests that data on smoking status obtained via EHRs tend to be incomplete or inaccurate, with implausible longitudinal changes observed (Polubriaginof et al., 2018). As hospitalised populations differ by age and sex from the general population (Secondary Care Analytical Team, 2020), comparisons of current and former smoking prevalence in hospitalised and non-hospitalised populations are likely biased. There is therefore a need for alternative study designs with relevant comparator groups and adjustment for covariates to better understand the association of smoking status with COVID-19 disease outcomes.\n\nHowever, the selection of an appropriate comparator group is not straightforward. Ideally, controls should represent the underlying population from which cases emerged, both geographically and demographically (Grimes and Schulz, 2005). In the context of COVID-19 hospitalisation, disease severity and death, we therefore reasoned a priori that historical controls – i.e. patients hospitalised at the same trust with another respiratory viral infection (e.g. influenza) a year previous – would act as a useful comparator, as they represent a geographically matched population at risk of severe disease from a circulating respiratory virus with a similar route of transmission (i.e. respiratory droplets and aerosols) and detection (i.e. laboratory-confirmed infection prior to or upon hospitalisation) (McCarthy and Giesecke, 1999). In addition, risk factors for hospitalisation with other respiratory viruses are similar to those for hospitalisation with COVID-19 (e.g. older age, comorbidities) (Falsey et al., 2014; Peralta et al., 2010).\n\nIn the present case-control study, we therefore first aimed to examine the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections (e.g. influenza, respiratory syncytial virus) a year previous at a single UK hospital trust. Second, we aimed to examine whether there is a discordance between smoking status recorded on the summary EHR and within the contemporaneous medical notes. As current smoking in April 2020 (when our study protocol was registered) was a priori expected to be associated with an increased risk of COVID-19 hospitalisation (Alqahtani et al., 2020; Simons et al., 2020), and with the association expected to be of a similar magnitude to that observed for other respiratory viruses, we opted for a non-inferiority design to test the hypothesis that the proportion of current smokers in patients hospitalised with COVID-19 is similar to that in patients hospitalised with other respiratory viral infections a year previous.\n\n\nMethods\n\nThis study was approved by the UCL/UCLH Joint Research Office Research Strategy Group and UCLH Data Access Committee. Approval to conduct research limited to pseudonymised patient data was provided by the NHS Health Research Authority (IRAS_282704). The requirement for informed consent was waived by the NHS Health Research Authority due to the observational nature of the study.\n\nThis was an observational case-control study with historical controls, performed at a single National Health Service (NHS) hospital trust (comprising two hospital sites) in London, UK. The study protocol and analysis plan were pre-registered on the Open Science Framework in April 2020 (Simons et al., 2020). The pre-registered protocol stipulated a non-inferiority design (i.e. a one-tailed statistical test) to maximise statistical power to detect a significantly lower proportion of current smokers (i.e. <10%) among patients hospitalised with COVID-19 compared with patients hospitalised with another respiratory viral infection a year previous (i.e. 20%). The protocol was amended after data collection but prior to statistical analysis in September 2020 to implement a traditional case-control design (i.e. a two-tailed statistical test), as a delay in study approval meant that the number of eligible cases and controls exceeded our expectations; providing sufficient power for a two-tailed test. We had also planned to compare current smoking in cases with age- and sex-matched London prevalence, with data obtained from the representative Annual Population Survey. However, following an external review on an earlier manuscript draft, we decided against presenting data from this comparison due to smoking rates in hospitalised populations typically being greater than in the general population (Benowitz et al., 2009).\n\nA sample size calculation, updated after data collection but prior to data analysis, indicated that 363 cases and 109 controls would provide 80% power to detect a 10% difference in current smoking prevalence in cases compared with controls (e.g. 10% in cases and 20% in controls) with alpha set to 5%. We included all cases from 1st March 2020 to the 26th August 2020 (the date on which data were obtained) and all controls from the 1st January 2019 and the 31st December 2019.\n\nInclusion criteria\n\nCases\n\n1. Consecutive patients admitted to an adult hospital ward (i.e. 18+ years) between 1st March 2020 and 26th August 2020 (the date on which data were obtained).\n\n2. Diagnosis of COVID-19 on or within five days of hospital admission, identified via associated International Classification of Diseases version 10 (ICD-10) codes (World Health Organisation, 2019). This temporal boundary was set to prevent inclusion of patents with nosocomial (hospital-acquired) infection and allowed for a delay of three days in requesting a COVID-19 test and two days for receiving and reporting the results on the EHR. The median incubation time for COVID-19 is estimated at 5.1 days (95% CI = 4.5-5.8) (Lauer et al., 2020). We sought to exclude individuals with nosocomial COVID-19 infection as they are a different population (e.g. older, more frail) compared with those infected in the community and subsequently requiring hospitalisation.\n\nControls\n\n1. Consecutive patients admitted to an adult hospital ward (i.e. 18+ years) between 1st January 2019 and 31st December 2019.\n\n2. Diagnosis of a viral respiratory infection (e.g. influenza, parainfluenza) on or within 5 days of admission, identified via ICD-10 codes.\n\nExclusion criteria\n\n1. No record of smoking status on the summary EHR or within the medical notes.\n\n2. A primary diagnosis of infectious exacerbation of chronic obstructive pulmonary disease (COPD) due to the strong causal association of COPD with current and former smoking.\n\n\nMeasures\n\nData on demographic and smoking characteristics were collected from the summary EHR or the medical notes. In the UK, the summary EHR is produced at the point of an individual's first interaction with a specific NHS hospital trust. Further information is added to the summary EHR following subsequent interactions with the hospital trust. The medical notes include contemporaneous clinical notes, General Practitioner referral letters and outpatient clinic letters, and are updated more frequently than the summary EHR.\n\nThe outcome of interest was the type of hospital admission (i.e. with COVID-19 vs. other respiratory viral infections a year previous).\n\nSmoking status (i.e. current, former, never) was obtained from the summary EHR or the medical notes. A number of cases were recorded as ‘non-smokers’ without distinguishing between ‘former smokers’ and ‘never smokers’. For the primary analysis, patients categorised as a ‘non-smoker’ were treated as ‘never smokers’. Where possible, information on use of smokeless tobacco, waterpipe and/or alternative nicotine products (e.g. e-cigarettes) was extracted. We searched within the contemporaneous medical records for free-text entries of smoking status. The most recently available record of smoking status, obtained from either the summary EHR or the medical notes, was extracted. Where available, data on pack-year history of smoking (i.e. the number of packs of cigarettes smoked per day multiplied by the number of years of smoking, with a pack equal to 20 cigarettes) were extracted.\n\nCovariates included age, sex, ethnicity, socioeconomic position (SEP; with post codes linked by the research team to the Index of Multiple Deprivation (IMD) (Department for Communities and Local Government, 2019)) and comorbidities (classified by organ system, including cardiac, metabolic and respiratory diseases). Medical conditions not expected to be strongly associated with COVID-19 hospitalisation were not considered in the analyses (e.g. sciatica and fibromyalgia; see Extended data). Age was treated as a continuous variable in the primary analysis, with banded age groups (i.e. 18-29 years, 30-44 years, 45-59 years, 60-74 years, 75-89 years and > 90 years) used in exploratory analyses. The IMD was categorised as quintiles to reduce the impact of sparse data.\n\n\nData analysis\n\nAll analyses were conducted in R version 4.0.2. (R Core Team, 2020). Descriptive statistics for cases and controls are reported. To explore differences between cases and controls, Pearson’s Chi-square tests, Cochran-Armitage tests for trend and ANOVAs were used, as appropriate.\n\nTo examine the association of former and current smoking with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections, unadjusted and two different adjusted generalised linear models with a binomial distribution and logit link function were performed. The first model adjusted for age, sex and SEP, with a second model adjusting for age, sex, SEP and comorbidities. We report odds ratios (ORs), 95% confidence intervals (CIs) and p-values. Two sensitivity analyses were subsequently performed. First, those recorded as ‘non-smokers’ were removed from the analysis. Second, those excluded from the analytic sample due to missing data on smoking status (see section above on ‘Exclusion criteria’) were included and coded as i) ‘never smokers’ and then as ii) ‘current smokers’ to assess the robustness of the associations.\n\nTo examine the concordance between smoking status recorded on the summary EHR and within the contemporaneous medical notes, Pearson’s Chi-squared tests were performed for the entire sample, and then separately for cases and controls.\n\n\nResults\n\nA total of 610 potential cases and 514 potential controls were identified. A total of 446 cases and 211 controls were included in the analytic sample (see Figure 1). In total, 13 potential controls and 60 potential cases were excluded due to not having a record of documented smoking status. This was likely due to patients having no prior contact with the NHS foundation trust. Notably, 37 (62%) potential cases that were excluded because of missing smoking status did not survive to hospital discharge, with no in-hospital mortality in potential controls, which suggests that data may be missing due to increased mortality in cases.\n\nCompared with controls, cases were more likely to be male (55% vs. 35.9%) and older (64.9 years vs 62.5 years) (see Table 1). Approximately 10% of cases and controls had missing data for ethnicity. Compared with cases, controls were more likely to be admitted from more deprived areas (IMD quintiles 1 and 2) (41.8% vs. 32.9%, p < 0.001). Cases were more likely than controls to have pre-existing metabolic (30.3% vs 13.3%) and cardiac comorbidities (53.4% vs 30.3%). A significantly larger proportion of cases compared with controls did not survive to discharge (28.7% vs. 4.3%). Among 128 cases not surviving to discharge, 53 (41.4%) were never smokers, 63 (49.2%) were former smokers and 12 (9.4%) were current smokers. For patients who survived to discharge, the median length of hospital stay for cases and controls was 9 (IQR = 4-18) and 4 (IQR = 2-9) days, respectively (see Table 1).\n\na IMD is not available for individuals with home addresses outside of England.\n\nCases and controls were predominantly admitted from North central and North East central London (see Extended data, Figure S1). The number of cases admitted from peripheral locations was greater than in controls and represents transfer of inpatients from other hospitals and diversion of patients that would otherwise have attended local hospitals due to bed pressures. The Chi-square test for trend found inconclusive evidence for any difference in SEP between cases and controls, χ2(3) = 8.93, p = 0.06 (see Extended data).\n\n\nAssociation of smoking status with type of hospitalisation\n\nThe prevalence of former smoking was higher in cases compared with controls (38.6% vs. 31.8%). Current smoking prevalence was lower in cases compared with controls (9.4% vs. 17.1%). A single patient from the case cohort was recorded as a dual cigarette and e-cigarette user. Two patients, one from each cohort, were recorded as dual cigarette and shisha/waterpipe users. Pack-year history of smoking was only recorded for 40% of patients with a smoking history (see Table 1).\n\nIn the univariable analysis, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (OR = 0.52, 95% CI = 0.31-0.86, p = 0.01). The odds for former smokers were equivocal (OR = 1.16, 95% CI = 0.81-1.68, p = 0.43).\n\nIn the multivariable analysis adjusted for sex, age and SEP, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (OR = 0.48, 95% CI = 0.28-0.83, p < 0.01). There was no significant association among former smokers (OR = 0.90, 95% CI = 0.61-1.34, p = 0.61). Results were not materially altered when also adjusting for relevant comorbidities (current smokers, OR = 0.55, 95% CI = 0.31-0.96, p = 0.04; former smokers, OR = 1.08, 95% CI = 0.72-1.61, p = 0.70).\n\n\nSensitivity analyses\n\nFirst, in a sensitivity analysis with patients recorded as ‘non-smokers’ excluded from the sample (leaving 398 cases and 159 controls), current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (OR = 0.41, 95% CI = 0.22-0.74, p = 0.03). There was no significant association among former smokers (OR = 0.78, 95% C.I. = 0.49-1.23, p = 0.28).\n\nSecond, in a sensitivity analysis with those with missing data on smoking status (n = 73) treated as ‘never smokers’ (resulting in 506 cases and 224 controls), patients hospitalised with COVID-19 had reduced odds of being a current smoker compared with those admitted with other respiratory viruses (OR = 0.51, 95% CI = 0.30-0.88, p = 0.01). Next, when those with missing data on smoking status were treated as ‘current smokers’, there was no significant association between current smoking and hospitalisation with COVID-19 (OR = 0.94, 95% CI = 0.61-1.46, p = 0.80).\n\n\nConcordance of smoking status recorded on the summary EHR and the medical notes\n\nControls were more likely to have no record of smoking status on the summary EHR compared with cases (75.4% vs. 7%) (see Figure 2). However, smoking status could be ascertained from the contemporaneous medical notes for all included cases and controls. Smoking status on the summary EHR (including ‘unknown’ status) was incorrectly recorded for 168 (79.6%) controls and 60 cases (13.5%) (χ2(3) = 226.7, p = < 0.001). In cases, six current smokers were misclassified as former smokers, one current smoker as a never smoker and six current smokers had no record of smoking status on the summary EHR. In controls, six current smokers were misclassified as former smokers and 23 current smokers had no record of smoking status on the summary EHR. There was greater discordance between smoking status recorded on the summary EHR and within the contemporaneous medical notes in controls (χ2(3) = 256.5, p = < 0.001) than in cases (χ2(3) = 34.2, p = < 0.001).\n\n\nDiscussion\n\nThis observational case-control study with patients admitted to a single UK hospital trust found a lower proportion of current smokers in cases hospitalised with COVID-19 during the first phase of the pandemic compared with controls hospitalised with other respiratory viral infections a year previous. Further, we found that smoking status is typically poorly recorded in the summary EHR. This was more prominent in controls than cases – a difference that is likely explained by the observation that COVID-19 patients were followed up by the respiratory medicine team after discharge, as part of a COVID-19 follow-up clinic where they specifically asked about smoking status (Mandal et al., 2020). The observed discrepancy between smoking status recorded on summary EHRs and the contemporaneous medical notes is a concern, particularly for studies relying solely on EHRs as the source of information on smoking status.\n\nTo our knowledge, this is one of few studies specifically designed to examine the association between smoking status and hospitalisation with COVID-19. It was further strengthened by an assessment of the quality of data on smoking status gleaned from summary EHRs.\n\nHowever, this study has several important limitations, the majority of which pertain to the selection of the controls. First, current smoking is expected a priori to be associated with hospitalisation for non-COVID-19 respiratory viruses (Stämpfli & Anderson, 2009). Ideally, hospital-based case-control studies should avoid selecting a control disease which is associated with the exposure of interest (i.e. smoking status) (Vandenbroucke & Pearce, 2012). However, to our knowledge, there is no other control disease with a similar route of acquisition and mechanism for hospitalisation/severe disease that is not a priori also associated with smoking status. The greater smoking prevalence in controls compared with the general population from which the cases emerged (Vandenbroucke & Pearce, 2012) therefore likely contributes to the significantly reduced odds of current smoking in our cases.\n\nSecond, the risk profile for controls likely differs from cases in that there is prior immunity to other respiratory viruses (e.g. influenza, respiratory syncytial virus), with no prior immunity in the population to SARS-CoV-2.\n\nThird, we selected the controls on the basis of sharing a similar route of transmission and risk factors for hospitalisation as cases. However, at the time of writing (March 2021), we now suspect that COVID-19 differs from other respiratory viruses in several ways. For example, COVID-19 gains cell entry via the ACE-2 receptor (Hoffmann et al., 2020), with unknown receptor binding in flu (Killingley & Nguyen-Van-Tam, 2013) and appears to display less fomite and physical contact transmission than flu (Ben-Shmuel et al., 2020). In addition, emerging evidence suggests that COVID-19 has a significantly different pathological process compared with other respiratory viruses. For example, mortality rates from COVID-19 differ widely from those due to epidemic influenza (Office for National Statistics, 2020a). Although we currently do not know the importance of these factors, taken together, emerging observations may mean that direct comparison of risk profiles in cases and controls is limited.\n\nFourth, while no known behavioural restrictions were implemented during the control period, London was under lockdown restrictions from March to July 2020, which likely impacted the risk of viral exposure in cases (Davies et al., 2020). This may further have impacted the different risk profiles of controls and cases beyond the adjustments made in this analysis for sex, age and SEP.\n\nFifth, the selection of historical controls may mean that there are non-trivial differences in smoking status between controls and cases due to a declining trend in London smoking prevalence (Office for National Statistics, 2020b). However, a single year was used for the selection of controls, and there was no large change in national smoking prevalence from 2019 to 2020 in England (Brown, 2020), so we expect any impact of the time-varying exposure to be minimal. We considered using a contemporaneous control (i.e. patients hospitalised with other respiratory viral infections in 2020), which would have mitigated against this potential bias. However, due to factors such as reduced national and international travel, physical distancing, increased hand hygiene and potential viral dominance by COVID-19, exposure to and hospitalisation with other respiratory viruses has been substantially reduced in 2020 (GOV.UK, 2020), which would have limited the sample size for controls.\n\nSixth, a history of current or past cancer was high in both groups at greater than 20% and was significantly greater in controls compared with cases. This reflects a bias in the population that regularly interacts with the selected NHS hospital trust, which is a specialist cancer referral centre. We visualised the geographic regions where patients were admitted from to examine any systemic differences between cases and controls, and caution that the differing catchment areas of the two cohorts may have led to important differences in the underlying populations. In addition, during the peak of the first wave of the pandemic in the UK (i.e. March-April 2020), many cases were transferred across hospital sites due to bed pressures (Dunhill, 2020).\n\nFinally, there was a greater proportion of cases than controls with no record of smoking status on either the summary EHR or within the contemporaneous medical notes (thus, they were not eligible for inclusion), with patients with missing data having unusually high mortality. It is plausible that many of them were smokers. We attempted to mitigate against this by conducting several sensitivity analyses, with the results largely remaining robust. However, when those excluded from the cohort due to missing data on smoking status were treated as current smokers, there was no significant association between current smoking and hospitalisation for COVID-19.\n\nDespite these limitations, alternative designs were impracticable or would have had different limitations. In the future, the current study can be considered alongside findings across multiple such alternative methodological approaches, each with different sources of bias, to triangulate on the extent to which associations between smoking and COVID-19 are causal.\n\nCOVID-19 will continue to place a large burden on healthcare services in the UK and internationally over the coming months and years. To mitigate against this, multiple non-pharmacological interventions are being implemented to reduce the intensity of demand on acute and intensive services. Irrespective of any direct link between smoking and COVID-19 disease outcomes, smoking is a significant cause for healthcare demand globally. We have argued elsewhere for the need to ramp up smoking cessation support to reduce the current and future burden on healthcare and social services (Simons et al., 2020).\n\nThe selection of appropriate controls in hospital-based case-control studies is very challenging for a novel respiratory virus such as COVID-19 (which means we converged on a hybrid approach, combining elements from hospital-based case series and case-control designs with historical controls). We recommend the use of representative population-studies with data from multiple sites and with purposeful acquisition of smoking status, to better understand the role of smoking as a potential risk or protective factor for COVID-19 hospitalisation and disease severity.\n\n\nConclusion\n\nIn a single hospital trust in the UK, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous, although we caution against interpreting this as a causal association. Smoking status was poorly recorded, with high observed discordance between smoking status recorded on the summary EHR and the contemporaneous medical notes.\n\n\nData availability\n\nDue to the sensitive nature of the data, we do not have ethical approval to release the individual-level data underpinning the analyses. Anonymised and de-identified individual-level data are available upon request from the corresponding author to bona fide researchers and following approval from the Biomedical Research Centre Clinical and Research Informatics Unit at University College London Hospital NHS foundation trust.\n\nOSF: Association of smoking status with hospitalisation for COVID-19 compared with other respiratory viruses a year previous: a case-control study at a single UK National Health Service trust: Protocol. https://doi.org/10.17605/OSF.IO/84VYD (Simons et al., 2021).\n\nThis project contains the following extended data:\n\n- Date file 1. (Extended data, PDF format)\n\n- Data file 2. (Protocol, docx format)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International (CC-By Attribution 4.0 International).",
"appendix": "References\n\nAlqahtani JS, Oyelade T, Aldhahir AM, et al.: Prevalence, Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis. PLoS ONE. 2020. 15. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBenowitz NL, Schultz KE, Haller CA, et al.: Prevalence of smoking assessed biochemically in an urban public hospital: a rationale for routine cotinine screening. Am. J. Epidemiol. 2009; 170: 885–891. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBen-Shmuel A, Brosh-Nissimov T, Glinert I, et al.: Detection and infectivity potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in isolation units and quarantine facilities. Clin. Microbiol. Infect. 2020; 26: 1658–1662. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrake SJ, Barnsley K, Lu W, et al.: Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). J Clin Med. 2020; 9: 841. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrown J: The Smoking Toolkit Study, 2020.2020. Reference Source\n\nCai G: Bulk and Single-Cell Transcriptomics Identify Tobacco-Use Disparity in Lung Gene Expression of ACE2, the Receptor of 2019-nCov.2020. Publisher Full Text Reference SourceReference Source\n\nDavies NG, Kucharski AJ, Eggo RM, et al.: Effects of non-pharmaceutical interventions on COVID-19 cases, deaths, and demand for hospital services in the UK: a modelling study. Lancet Public Health. 2020; 5: e375–e385. Publisher Full Text\n\nDepartment for Communities and Local Government: The English Indices of Deprivation 2019 31.2019.\n\nFalsey AR, McElhaney JE, Beran J, et al.: Respiratory Syncytial Virus and Other Respiratory Viral Infections in Older Adults With Moderate to Severe Influenza-like Illness. J. Infect. Dis. 2014; 209: 1873–1881. Publisher Full Text\n\nFang L, Karakiulakis G, Roth M: Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020. 0. Publisher Full Text\n\nGOV.UK: Weekly national flu and COVID-19 surveillance reports published [WWW Document]. GOV.UK. 2020. (accessed 3.11.21).Reference Source\n\nGrimes DA, Schulz KF: Compared to what? Finding controls for case-control studies. Lancet. 2005; 365: 1429–1433. Publisher Full Text\n\nGuan W, Liang W, Zhao Y, et al.: Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur. Respir. J. 2020; 55. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoffmann M, Kleine-Weber H, Schroeder S, et al.: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181: 271-280.e8. Publisher Full Text\n\nJohns Hopkins Coronavirus Resource Center: COVID-19 Map [WWW Document]. Johns Hopkins Coronavirus Resour. Cent. 2021. (accessed 3.11.21).Reference Source\n\nKillingley B, Nguyen-Van-Tam J: Routes of influenza transmission. Influenza Other Respir. Viruses. 2013; 7(Suppl 2): 42–51. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLauer SA, Grantz KH, Bi Q, et al.: The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann. Intern. Med. 2020; 172: 577–582. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMandal S, Barnett J, Brill SE, et al.: ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax. 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcCarthy N, Giesecke J: Case-case comparisons to study causation of common infectious diseases. Int. J. Epidemiol. 1999; 28: 764–768. PubMed Abstract | Publisher Full Text\n\nOakes JM, Fuchs RM, Gardner JD, et al.: Nicotine and the renin-angiotensin system. Am J Physiol - RegulIntegr Comp Physiol. 2018; 315: 895–906. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOffice for National Statistics: Deaths due to coronavirus (COVID-19) compared with deaths from influenza and pneumonia, England and Wales [WWW Document].2020a. (accessed 10.29.20). Reference Source\n\nOffice for National Statistics: Adult smoking habits in the UK: 2019, Annual Population Survey.Office for National Statistics; 2020b.\n\nPeralta PS-O, Cortes-García M, Vicente-Herrero M, et al.: Risk factors for disease severity among hospitalised patients with 2009 pandemic influenza A (H1N1) in Spain, April – December 2009. Eurosurveillance. 2010; 15: 19667. PubMed Abstract | Publisher Full Text\n\nPolubriaginof F, Salmasian H, Albert DA, et al.: Challenges with Collecting Smoking Status in Electronic Health Records. AMIA. Annu. Symp. Proc. 2018; 2017: 1392–1400. PubMed Abstract | Free Full Text\n\nR Core Team: R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. 2020.\n\nSecondary Care Analytical Team: Hospital Admitted Patient Care Activity 2019-20. Hospital Admitted Patient Care Activity. 2020.\n\nSimons D, Perski O, Brown J: Covid-19: The role of smoking cessation during respiratory virus epidemics. The BMJ. 2020.\n\nSimons D, Shahab L, Brown J, et al.: The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review with Bayesian meta-analyses (version 11). Qeios. 2021. Publisher Full Text\n\nStämpfli MR, Anderson GP: How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat. Rev. Immunol. 2009; 9: 377–384. PubMed Abstract | Publisher Full Text\n\nVandenbroucke JP, Pearce N: Case–control studies: basic concepts. Int. J. Epidemiol. 2012; 41: 1480–1489. PubMed Abstract | Publisher Full Text\n\nWorld Health Organisation: ICD-10 [WWW Document].2019. (accessed 10.28.20).Reference Source"
}
|
[
{
"id": "92725",
"date": "13 Sep 2021",
"name": "Maria Rosaria Galanti",
"expertise": [
"Reviewer Expertise Epidemiology",
"tobacco use"
],
"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 was a case-control study aiming at shedding light on the potential causal association between tobacco smoking and hospitalization because of COVID-19. In the light of the controversial associations between smoking and risk for infection with SARS-COV-2 on the one side, clinical disease and its severity on the other side, the contribution has a great interest. The manuscript is clearly and soundly written, and the results are thoughtfully discussed within a series of sensitivity analyses.\nHowever, the several weaknesses in the design and assessment of exposure, with corresponding risk for bias (to be sure, fully acknowledged by the authors) did not allow the attainment of the study's goal. Besides the weaknesses already addressed by the authors, the following points should be considered, bearing in mind that in a case-control study the concern is on characteristics being different or differentially assessed in the case and in the referent series and possibly associated with the exposure:\nCan we assume that the procedure for hospital admissions for COVID-19 was the same as for other respiratory infections one year earlier (see page 6, lines 3-4)? To my knowledge, hospital admission routines during the pandemic were profoundly disrupted in many countries, with patient transfer between hospitals, different priorities of admission, etc. Even if not explicitly, some of the patient characteristics correlated with smoking may have determined different patient selection and/or ascertainment of smoking.\n\nCould the assessment of smoking at the point of hospitalization among COVID-19 patients be biased by the pandemic or by the disease? Starting from March 2020, much attention was drawn on smoking, causing adverse outcomes in COVID-19 hospitalized patients, a position even endorsed by the WHO later in Spring 2020 (https://www.who.int/news-room/commentaries/detail/smoking-and-covid-19). Thereafter, some smokers (especially if already suffering from smoking-related diseases) may have quit before hospital admission or may have concealed their smoking to the healthcare staff. Also, the accuracy of the staff assessing smoking behavior may have varied depending on the severity of the disease. This risk is supported by the notation that the COVID-19 patients with unknown smoking status (more numerous than among the referent cases) had higher mortality than those with a full assessment of smoking. Following the premises in the introduction (logical expectation of higher risk among smokers), it would be sensible to assume that among these “unknown smoking” patients the proportion of smokers would be higher. When tested in a sensitivity analysis, this assumption made the inverse association smoking-COVID-19 hospital admission weaken/disappear (page 8).\n\nThe adjustment for SEP was done on the ecologic level. This may have introduced bias (over-adjustment for opportunity of infection, including due to high smoking prevalence?) if the rate of infection/hospital admission with SARS-COV-2 was differently clustered in socio-economically disadvantaged areas compared to affluent areas, at odds with the more “widespread” diffusion of other respiratory infections.\nSome minor points:\nI would avoid the notation “case cohort” and “control cohort” (page 6), which is misleading, using rather “case series” or “case sample”.\n\nI would rephrase the conclusions as “…patients hospitalized with COVID-19 had lower odds of appearing as smokers compared with patients... “, which is more respectful of what was actually analyzed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7403",
"date": "15 Nov 2021",
"name": "Olga Perski",
"role": "Author Response",
"response": "This was a case-control study aiming at shedding light on the potential causal association between tobacco smoking and hospitalization because of COVID-19. In the light of the controversial associations between smoking and risk for infection with SARS-COV-2 on the one side, clinical disease and its severity on the other side, the contribution has a great interest. The manuscript is clearly and soundly written, and the results are thoughtfully discussed within a series of sensitivity analyses. Thank you for the constructive feedback on our manuscript, which we believe has helped strengthen it. However, the several weaknesses in the design and assessment of exposure, with the corresponding risk for bias (to be sure, fully acknowledged by the authors) did not allow the attainment of the study's goal. Besides the weaknesses already addressed by the authors, the following points should be considered, bearing in mind that in a case-control study the concern is on characteristics being different or differentially assessed in the case and in the referent series and possibly associated with the exposure: Can we assume that the procedure for hospital admissions for COVID-19 was the same as for other respiratory infections one year earlier (see page 6, lines 3-4)? To my knowledge, hospital admission routines during the pandemic were profoundly disrupted in many countries, with patient transfer between hospitals, different priorities of admission, etc. Even if not explicitly, some of the patient characteristics correlated with smoking may have determined different patient selection and/or ascertainment of smoking. Could the assessment of smoking at the point of hospitalization among COVID-19 patients be biased by the pandemic or by the disease? Starting from March 2020, much attention was drawn on smoking, causing adverse outcomes in COVID-19 hospitalized patients, a position even endorsed by the WHO later in Spring 2020 (https://www.who.int/news-room/commentaries/detail/smoking-and-covid-19). Thereafter, some smokers (especially if already suffering from smoking-related diseases) may have quit before hospital admission or may have concealed their smoking to the healthcare staff. Also, the accuracy of the staff assessing smoking behavior may have varied depending on the severity of the disease. This risk is supported by the notation that the COVID-19 patients with unknown smoking status (more numerous than among the referent cases) had higher mortality than those with a full assessment of smoking. Following the premises in the introduction (logical expectation of higher risk among smokers), it would be sensible to assume that among these “unknown smoking” patients the proportion of smokers would be higher. When tested in a sensitivity analysis, this assumption made the inverse association smoking-COVID-19 hospital admission weaken/disappear (page 8). Thank you - we have now reflected on these important points in the limitations section on p.12: “Fifth, hospital admission routines were severely disrupted in many countries during the early stages of the COVID-19 pandemic (e.g., patient transfer between hospitals, altered admission criteria). This may have influenced patient selection and/or the recording of smoking status. With regards to patient selection, albeit possible, we are unaware of evidence from UK hospitals of patient characteristics correlated with smoking (e.g., age, SEP) determining whether a patient would be admitted, rather than their clinical situation on presentation. For example, smoking status has not been included in a widely used hospital-based algorithm for predicting clinical deterioration from COVID-19 (i.e., the ISARIC-4C deterioration score; Gupta et al., 2021). With regards to the recording of smoking status, to the best of our knowledge, the admission routines (including the medical history taking) within the selected hospital trust remained stable during the pandemic. However, patients admitted with COVID-19 may generally have been more unwell at the point of admission compared with controls, which may have led to less accurate documentation of smoking status. This potential bias was somewhat reduced by those surviving their COVID-19 illness being followed up through a specialised respiratory medicine clinic implemented during the pandemic, with smoking status ascertained during follow-up calls/visits. However, the finding that COVID-19 patients with unknown (compared with those with recorded) smoking status had greater in-hospital mortality means that residual bias cannot be ruled out. A sensitivity analysis with all missing assumed to be current smokers made the negative association of smoking status and COVID-19 hospital admission go away. However, it should be noted that this is a very strong assumption, unlikely to hold true.” The adjustment for SEP was done on the ecologic level. This may have introduced bias (over-adjustment for the opportunity of infection, including due to high smoking prevalence?) if the rate of infection/hospital admission with SARS-COV-2 was differently clustered in socio-economically disadvantaged areas compared to affluent areas, at odds with the more “widespread” diffusion of other respiratory infections. To investigate the role of SEP as a potential confounder in our analysis, we have now conducted an additional sensitivity analysis removing SEP from the multivariable model (reported on p.10). In the sensitivity analysis with sex and age only, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (OR = 0.51, 95% CI = 0.31-0.86, p = 0.01). There was no significant association among former smokers (OR = 0.95, 95% CI = 0.65-1.40, p = 0.80). These were similar to the analyses including SEP (OR = 0.48, 95% CI = 0.28-0.83, p < 0.01 and OR = 0.90, 95% CI = 0.61-1.34, p = 0.61, respectively). Some minor points: I would avoid the notation “case-cohort” and “control cohort” (page 6), which is misleading, using rather “case series” or “case sample”. Thank you for pointing out this difference – we have now changed to “case sample” throughout. I would rephrase the conclusions as “…patients hospitalized with COVID-19 had lower odds of appearing as smokers compared with patients... “, which is more respectful of what was actually analyzed. This has now been amended accordingly."
}
]
},
{
"id": "94125",
"date": "08 Oct 2021",
"name": "Jonathan M. Samet",
"expertise": [
"Reviewer Expertise Pulmonary disease",
"epidemiology",
"tobacco control"
],
"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\nGeneral Comments:\nThis paper describes the findings of a hospital-based case-control study on cigarette smoking on risk for hospitalization from COVID-19. The paper is lacking a clear explication of the underlying hypothesis, which is critical to determining what is the appropriate control group. Smoking might influence the risk of becoming infected with SARS-CoV-2; and/or the risk of more severe disease given infection, which could lead to increased risk for hospitalization and death. The effects of smoking on airway receptors could plausibly effect risk for infection and modify its severity, as could the effects of smoking on the lungs and its causation of non-communicable diseases.\n\nThe authors write extensively about the problems of control group selection but, lacking a clearly focused hypothesis, their discussion is general. If the question is whether smoking affects the risk of hospitalization, given infection, then the appropriate control group comprises non-hospitalized, SARS-CoV-2 infection who were not hospitalized. If the question related to risk for infection, than the appropriate control group has comparable exposure but without becoming infected.\n\nThe authors turn to a problematic historical control group of individuals hospitalized with other respiratory infections during a pre-pandemic time period. How this control group relates to the potential hypotheses is unclear. Additionally, there may have been pandemic-related trends in smoking that would not be taken into account. Additionally, smoking increases risk for respiratory infections generally (see 2014 report of the US Surgeon General1), further complicating interpretation of the results.\n\nWhy is SEP included in the model? It is a powerful predictor of smoking and of co-morbidities, but is it a likely confounder and why?\n\nWere the cases all diagnosed with COVID-19? What about those admitted for other reasons, but testing positive for SARS-CoV-2 on admission?\nThe discussion does not adequately integrate this new study into existing literature, including ongoing systematic reviews.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "7404",
"date": "15 Nov 2021",
"name": "Olga Perski",
"role": "Author Response",
"response": "This paper describes the findings of a hospital-based case-control study on cigarette smoking on risk for hospitalization from COVID-19. The paper is lacking a clear explication of the underlying hypothesis, which is critical to determining what is the appropriate control group. Smoking might influence the risk of becoming infected with SARS-CoV-2; and/or the risk of more severe disease given infection, which could lead to increased risk for hospitalization and death. The effects of smoking on airway receptors could plausibly effect risk for infection and modify its severity, as could the effects of smoking on the lungs and its causation of non-communicable diseases. The authors write extensively about the problems of control group selection but, lacking a clearly focused hypothesis, their discussion is general. If the question is whether smoking affects the risk of hospitalization, given infection, then the appropriate control group comprises non-hospitalized, SARS-CoV-2 infection who were not hospitalized. If the question related to risk for infection, than the appropriate control group has comparable exposure but without becoming infected. The authors turn to a problematic historical control group of individuals hospitalized with other respiratory infections during a pre-pandemic time period. How this control group relates to the potential hypotheses is unclear. Thank you for the constructive feedback on our paper, which we believe have helped strengthen it. We agree that the selection of controls ultimately mixes two potential mechanisms through which smoking status may influence COVID-19 outcomes (i.e., comparable exposure leading to differential infection rates and/or comparable infection rates leading to differential hospitalisation rates). As elaborated on in the discussion, and now clarified in the introduction on p.4-5, we selected the controls on the basis of sharing a similar route of transmission (i.e., influenza) and risk factors for hospitalisation as cases. Since planning this study in early 2020, the research community has learnt more about COVID-19 infection and disease mechanisms, and we have ourselves taken more care to map out potential causal pathways that need to be considered when planning studies to examine the relationship of smoking status and COVID-19 infection/disease to avoid confounding (see Perski et al., 2021). We now discuss these considerations and the issues with the selection of the controls on p.13-14: “Finally, we have argued elsewhere that studies that aim to elucidate the potential causal relationship between smoking status and COVID-19 should first clarify the mechanism(s) through which smoking and/or nicotine use is expected to influence COVID-19 infection and/or disease outcomes contingent on infection and plan their studies accordingly (Perski et al., 2021). Considering these reflections, and following constructive peer review, we acknowledge that the present study through its selection of the control sample does not distinguish between two potential mechanisms: comparable exposure to SARS-CoV-2 virus with differential infection in current compared with never smokers, and comparable SARS-CoV-2 infection with differential hospitalisation in current compared with never smokers. Future research should aim to isolate these potential mechanisms by design, thus getting closer to unbiased estimates of the association of smoking/nicotine use with COVID-19 outcomes. However, we note that – given the time-varying dynamics of respiratory viruses – it would be incredibly challenging to design a representative study to compare rates of infection in those with similar exposure using available datasets. Similarly, as data linkage of representative infection surveys with hospital records is also limited at present, designing a study to examine the second potential pathway (i.e., examining hospitalisation rates in a representative sample of those infected) would also be very challenging.” Additionally, there may have been pandemic-related trends in smoking that would not be taken into account. With regards to pandemic-related trends in smoking, we have now added the following to the discussion on p.14: “However, a single year was used for the selection of controls, and there was no significant change in smoking prevalence among all adults in England between immediately before and early in the pandemic (Apr-Jul 2020, Jackson et al., 2020), so we expect any potential impact of pandemic-related trends in smoking prevalence on the results to be minimal.” Additionally, smoking increases the risk for respiratory infections generally (see 2014 report of the US Surgeon General1), further complicating interpretation of the results. As the controls came from a similar population (i.e., individuals at risk of infection and hospitalisation with a circulating respiratory disease), we believe this was a strength in their selection. We have therefore not seen it necessary to discuss this beyond what is already mentioned about the selection of the control sample. Why is SEP included in the model? It is a powerful predictor of smoking and of co-morbidities, but is it a likely confounder, and why? SEP was included as a potential confounder due to being a strong predictor of both smoking and COVID-19 hospitalisation. In response to a similar comment from Reviewer 1, we have now included a sensitivity analysis with SEP removed (reported on p.10), with results remaining similar. Were the cases all diagnosed with COVID-19? What about those admitted for other reasons, but testing positive for SARS-CoV-2 on admission? Thank you for highlighting – all patients included in the case series had PCR confirmed infection with COVID-19. Given the broad and currently poorly understood COVID-19 pathology following infection, it was not possible to exclude patients with incident positive tests based on their presenting symptoms to ensure the exclusion of those testing positive upon admission to hospital who were admitted for reasons other than COVID-19. This is an important potential source of bias and we have now included the following in the limitations on p.13: “Seventh, given the broad and currently poorly understood COVID-19 pathology following SARS-CoV-2 infection, it was not possible to differentiate patients presenting to hospital due to COVID-19 or those admitted for other reasons. This may have introduced additional bias in that individuals may have been admitted to hospital with co-incident SARS-CoV-2 infection that was not associated with their current health need. We tried to mitigate this by only including cases if they had a positive COVID-19 test result less than 5 days from their date of hospital admission.” The discussion does not adequately integrate this new study into existing literature, including ongoing systematic reviews. We have now included a paragraph in the discussion on p.11 which highlights how our findings compare with those from an ongoing systematic review: “A living review and unadjusted Bayesian meta-analyses of observational studies conducted during the COVID-19 pandemic, up-to-date as of July 2021, has found that current smokers appear to be at reduced risk of COVID-19 infection, but that there is inconclusive evidence of an increased risk of more severe disease among smokers who are infected. In addition, former smokers appear to be at increased risk of severe disease and mortality from COVID-19 (Simons et al., 2020; Simons et al., 2021).”"
}
]
}
] | 1
|
https://f1000research.com/articles/10-846
|
https://f1000research.com/articles/10-256/v1
|
30 Mar 21
|
{
"type": "Method Article",
"title": "A deep learning segmentation strategy that minimizes the amount of manually annotated images",
"authors": [
"Thierry Pécot",
"Alexander Alekseyenko",
"Kristin Wallace",
"Alexander Alekseyenko",
"Kristin Wallace"
],
"abstract": "Deep learning has revolutionized the automatic processing of images. While deep convolutional neural networks have demonstrated astonishing segmentation results for many biological objects acquired with microscopy, this technology's good performance relies on large training datasets. In this paper, we present a strategy to minimize the amount of time spent in manually annotating images for segmentation. It involves using an efficient and open source annotation tool, the artificial increase of the training data set with data augmentation, the creation of an artificial data set with a conditional generative adversarial network and the combination of semantic and instance segmentations. We evaluate the impact of each of these approaches for the segmentation of nuclei in 2D widefield images of human precancerous polyp biopsies in order to define an optimal strategy.",
"keywords": [
"Deep learning",
"image annotation",
"semantic and instance segmentations",
"conditional GANs",
"nuclei segmentation"
],
"content": "Introduction\n\nOver the last decade, deep learning approaches have outperformed all existing methods for image segmentation1–4. Semantic segmentation, the estimation of a label at each pixel, and instance segmentation, the identification of individual objects, were successfully applied to spatially characterize biological entities in microscopic images5–8. However, these powerful approaches rely on large annotated datasets. While more and more datasets become publicly available9,10, annotated data for every combination of modalities, tissues and biological objects is far from completion. Therefore, procedures to efficiently build training datasets are re quired to use the full potential of deep learning-based segmentation at a single biological lab scale.\n\nIn this paper, we propose a strategy to minimize the amount of time dedicated to manually annotate images and investigate several approaches to maximize accuracy when only using one annotated image. We apply this strategy to segment nuclei stained with DAPI in widefield images of human colorectal adenomas (i.e. precancerous polyps) as follows. First, we take advantage of existing training datasets11,12 and massive data augmentation to obtain a preliminary segmentation. We then use an open source annotation software12 to manually correct this segmentation and consequently define the training dataset. Next, we simulate synthetic images using a conditional generative adversarial network (GAN)13 to increase the size of the training dataset. Finally, we combine U-Net14,15, a semantic segmentation approach, and Mask R-CNN16, an instance segmentation approach, to improve the nuclear segmentation accuracy.\n\n\nMethods\n\nIn this study, we used the Medical University of South Carolina (MUSC) pathology laboratory information system CoPath (Cerner Corporation, Kansas City, MO), to identify a convenience sample of colorectal adenomas excised from patients who underwent a sigmoidoscopy or colonoscopy with polypectomy between October 2012 and May 2016. For each patient, we obtained a formalin-fixed, paraffin-embedded (FFPE) tissue block and prepared one H&E and 5, 5-micron sections for immunofluorescence (IF) on FFPE tissue. Prior to the start of the IF procedures, all antibodies were optimized and reviewed by the study immunologist, the pathologist, the epidemiologist, and laboratory personnel to ensure agreement and proper staining. The MUSC Institutional Review Board has approved the research study (IRB # PRO-00007139).\n\nDAPI was used for nuclear counterstaining. Stained slides were mounted with ProLong™ Gold Antifade Reagent (Cat. # P36934, ThermoFisher) and imaged using the Akoya Vectra® Polaris™ Automated Imaging system (Akoya Biosciences, Marlborough, MA). Whole slide scans were done at 20X magnification and regions of interest where chosen randomly.\n\nU-Net, Mask R-CNN and pix2pix were coded in Python and used the Python libraries numpy17, tensorflow18, keras19, scipy20 and scikit-image21.\n\nThe training dataset consisted of three 1868 x 1400 images manually annotated with Annotater12. Only one image was used to train U-Net and Mask R-CNN as well as pix2pix (conditional GAN) for most of the study. The two other images were added to the training dataset in the last section to be compared with the combination of results obtained with U-Net and Mask R-CNN (see Figure 3).\n\nThe annotated 1868 x 1400 image was divided into six 622 x 700 images for training: five of these images were included in the training dataset while the last one defined the validation dataset. As U-Net is a semantic segmentation approach, three classes were defined to allow separating nuclei as proposed in 22: inner nuclei, nuclei contours and background. To facilitate nuclei separation, the nuclei contours in the training dataset were dilated22. To limit over-fitting, the imaging field for images in the training dataset was set to 256 x 256 by randomly cropping the 622 x 700 input images. These cropped images were then normalized to obtain intensity values between 0 and 1. A root mean square prop was used to estimate the parameters of the deep convolutional neural network by minimizing a weighted cross entropy loss to handle class imbalance for 100 epochs without data augmentation and 25 epochs with data augmentation. The weights associated with each class were defined from the training dataset as their inverse proportion. A data augmentation to increase the training dataset by a factor of 100 was processed after normalization with the imgaug python library23 and included flipping, rotation, pixel dropout, blurring, noise addition and contrast modifications. In Figure 2 and Figure 3, augmented simulated images were obtained by applying the same modifications with the imgaug python library to simulated images with pix2pix. When combining the annotated image for this study with simulated images and/or existing datasets, the number of augmented images was defined to be balanced between the different data.\n\nAn ImageJ macro24,25 was used to convert the three classes obtained with U-Net to individual nuclei. More specifically, individual nuclei were identified by thresholding the subtraction of the nuclei contours component from the inner nuclei component with a threshold equal to 0.35. A 3D Voronoi tessellation26 was then applied to assign each pixel to a nucleus. The object component was defined as all pixels whose background component was inferior to 0.95. This object component was then multiplied by the Voronoi tessellation to obtain individual nuclei. The Voronoi tessellation implies that a 1-pixel width area between nuclei is not assigned to any nucleus. To address this problem, the location of these pixels is obtained by subtracting the binary thresholding of the individual nuclei from the object component. The individual nuclei are then dilated27 and multiplied to this subtraction to be added to the individual nuclei. Finally, nuclei with less than 35 pixels were removed.\n\nThe annotated 1868 x 1400 image was divided into thirty-five 266 x 280 images for training: thirty of these images were included in the training dataset while the last five images defined the validation dataset. Version 2.1 of Mask R-CNN16 was used in this study. The backbone network was defined as the Resnet-101 deep convolutional neural network28. We used the code in 5 to define the only class in this study, i.e. the nuclei. A data augmentation to increase the training dataset by a factor of 100 was processed before normalization with the imgaug python library23 and included resizing, cropping, flipping, rotation, shearing, pixel dropout, blurring, sharpness and brightness modifications, noise addition and contrast modifications. Transfer learning with fine-tuning from a network trained on the coco dataset29 was also applied. In the first epoch, only the region proposal network, the classifier and mask heads were trained. The whole network was then trained for the next three epochs. In Figure 2 and Figure 3, augmented simulated images were obtained by applying the same modifications with the imgaug python library to simulated images with pix2pix. When combining the annotated image for this study with simulated images and/or existing datasets, the number of augmented images was defined to be balanced between the different data. The maximum image size used for processing Mask R-CNN was larger than 256 as resizing and cropping were applied for data augmentation and set to 512. This parameter was defined as 1024 when other existing datasets were included for training as magnification in these images is higher.\n\nOne 1868 × 1400 and one 934 × 1400 manually annotated images were used for evaluation. As proposed in 11, we used the F1 score with respect to the Intersection over Union (IoU) to evaluate the different nuclei segmentation approaches. More formally, let OGT = {OGT(e)}e=1,...,n be the set of n ground truth nuclei and OE = {OE(e)}e=1,...,m be the set of m estimated nuclei. The IoU defined between the truth nucleus OGT(e1) and the estimated nucleus OE(e2) was defined as:\n\n\n\nAn IoU (OGT(e1), OE(e2)) equal to 0 implies that OGT(e1) and OE(e2) do not share any pixel while an IoU (OGT(e1), OE(e2)) equal to 1 means that OGT(e1) and OE(e2) are identical. To ensure that one ground truth nucleus is not associated to multiple estimated nuclei and conversely, we use the following definition for the IoU:\n\n\n\nF1 score for a given IoU* threshold t > 0 can be defined as:\n\n\n\nwhere\n\n\n\nand\n\n\n\nWith a threshold t = 0.05, this metric gives the accuracy of a method to identify the correct number of nuclei, while with thresholds in the range 0.05 − 0.9, it evaluates the localization accuracy of the identified nuclear contours.\n\nThe annotated 1868 × 1400 image was divided into thirty-five 256 × 256 images for training. As defined in 13, U-Net14 was used for the generator and a convolutional PatchGAN classifier was used for the discriminator. Once trained, nuclei masks had to be generated to simulate images. Distributions for the number of nuclei per image and the size of nuclei were defined from the training dataset. The number of nuclei per image was then modeled as a Gaussian distribution while the size of nuclei was modeled by a Gumbel distribution to reflect the heavy tail distribution observed in the training dataset. Nuclei masks were then defined as ellipses randomly generated with these distributions with random orientation and a ratio between the two axes defined according to a Gaussian distribution of average s/π and standard deviation of 0.2s/π, where s is the area of the ellipse. 1000 256 × 256 nuclei images were simulated by considering the generated ellipses as nuclei masks.\n\nThe combination of results obtained with instance and semantic segmentations was initialized as the nuclei segmented with Mask R-CNN. To prevent from hallucinations, nuclei identified with Mask R-CNN for which the area overlapping with nuclei obtained with U-Net was inferior to 20% were discarded. Then, nuclei identified with U-Net whose area overlapping with nuclei obtained with Mask R-CNN was inferior to 33% were added as new nuclei to the final segmentation. Finally, nuclei with an area inferior to 35 pixels were discarded.\n\n\nResults\n\nA training dataset is required to train a deep learning method for object segmentation. Consequently, users most often start with manually annotating objects of interest with existing annotation tools30,31. As shown in Figure 1a, this task is particularly challenging in our case due to the wide range of morphologies and high density of nuclei in polyps. We use the ImageJ plugin Annotater12 to efficiently annotate nuclei, a task that takes approximately 30 hours. To avoid a fully manual annotation and save time, it is possible to use the same plugin to correct a nuclei segmentation obtained with an existing method. The watershed method32, probably the most used method for nuclei segmentation in fluorescence microscopy images, correctly identifies a high number of nuclei (high F1 score for a low IoU threshold in Figure 1 b-c). Unfortunately, under- and over-segmentations, a well-known limitation of this approach, lead to a poor segmentation localization (rapidly decreasing F1 score with increasing IoU thresholds in Figure 1 b-c). Alternatively, deep learning approaches can be trained with existing training datasets. We propose to use a high throughput chemical screen on U2OS cells dataset (CC) (image set BBBC039v1 available from the Broad Bioimage Benchmark Collection9) and a widefield mouse intestinal epithelium dataset (MIE)12. While U-Net demonstrates a poor performance with these datasets (Figure 1b), Mask R-CNN identifies more nuclei and mostly leads to much higher localization precision than the watershed approach (slowly decreasing F1 score with increasing IoU thresholds in Figure 1c). Correcting this segmentation with Annotater takes about 15–20 hours, which is clearly faster than an annotation from scratch. For both U-Net and Mask R-CNN, a massive data augmentation (100 times) clearly improves the performance.\n\na Widefield acquisition of a human polyp biopsy stained with DAPI. Manually annotated nuclei are overlaid as red circles. Zoomed-in regions are displayed on the right side with corresponding squared colors. Scale bar = 100µm. b–c F1 score for range of IoU thresholds obtained with the watershed method, with U-Net b and Mask R-CNN c approaches trained with a high-throughput chemical screen on U2OS cells dataset (CC) or/and a widefield mouse intestinal epithelium dataset (MIE), with and without data augmentation (DA). Lines correspond to average F1 score over the two tested images while the shaded areas represent the standard deviation.\n\na First row: masks generated as ellipses (see Methods) and represented with unique colors. Second row: images simulated from masks shown in first row with a conditional Generative Adversarial Network (GAN). b–c F1 score for range of IoU thresholds obtained with U-Net b and Mask R-CNN c trained with 1 annotated image with data augmentation (DA), 1000 simulated images, 1000 augmented simulated images, 1 annotated image with DA combined with 1000 augmented simulated images and 1 annotated image with DA combined with 1000 augmented simulated images as well as a high-throughput chemical screen on U2OS cells dataset (CC) and a widefield mouse intestinal epithelium dataset (MIE). Lines correspond to average F1 score over the two tested images while the shaded areas represent the standard deviation.\n\nF1 score for range of IoU thresholds obtained with U-Net trained with 1 and 3 annotated images with data augmentation (DA), Mask R-CNN trained with 1 and 3 annotated images with DA, and the combination of results obtained with U-Net trained with 1 annotated image with DA and augmented simulated images, and the results obtained with Mask R-CNN trained with 1 annotated image with DA, augmented simulated images and existing datasets with DA. Lines correspond to average F1 score over the two tested images while the shaded areas represent the standard deviation.\n\nSegmented nuclei obtained by combining U-Net and Mask R-CNN overlaid as red circles over the processed image. Zoomed-in regions are displayed on the right side with corresponding squared colors. Scale bar = 100µm.\n\nWhen only considering the annotated image in Figure 1a in the training dataset, U-Net leads to higher segmentation accuracy than Mask R-CNN (Figure 2a-b). To increase the training dataset, we use the same annotated image to train a conditional Generative Adversarial Network (GAN)13 and simulate images showing nuclei from masks defined as random ellipses generated with the distributions of nuclei size and nuclei number observed in the training dataset (see Figure 2c and Methods). Only using simulated images lead to a lower accuracy for both deep learning approaches, even though applying mathe matical operations to these synthetic images (augmented simulated training dataset, see Methods) improves the segmentation accuracy. However, pooling together augmented simulated images and the annotated image from Figure 1a slightly improves U-Net performance and distinctly increases the number of accurately identified nuclei with Mask R-CNN while decreasing the segmentation localization precision. Finally, adding existing datasets clearly leads to the optimal results for Mask R-CNN while degrading the accuracy for U-Net, which is consistent with the inability for this approach to generalize nuclear segmentation for different data as shown in Figure 1b.\n\nNuclei segmented with Mask R-CNN show a higher localization precision than those obtained with U-Net as shown in Figure 1a-b. However, nuclei that are harder to delineate are missed with Mask R-CNN while U-Net accurately identifies pixels that belong to nuclei, even though the separation between individual nuclei might not be precise. In order to get the best of both worlds, we propose to combine the results obtained with U-Net trained with one annotated image with data augmentation and augmented simulated images, and the results obtained with Mask R-CNN trained with one annotated image with data augmentation, augmented simulated images and existing datasets with data augmentation (see Methods). As shown in Figure 3, these results demonstrate a higher F1 score for any IoU threshold than obtained with U-Net or Mask R-CNN trained with 3 times more annotated images. The corresponding segmented nuclei are shown in Figure 4.\n\n\nDiscussion\n\nThis study demonstrates how to take advantage of existing training datasets, efficient annotation tools, massive data augmentation, conditional GANs and the combination of results obtained with both semantic and instance segmentations to minimize the amount of manually annotated data. When facing a new object segmentation problem, it is beneficial to find existing training datasets, even though modalities and/or tissues differ, to train an instance segmentation-based deep learning method. The segmentation obtained with this approach is then used to initialize a training dataset. Training a conditional GAN to increase the size of the training dataset improves the performance for both semantic and instance segmentations. Additionally, adding existing training datasets increases even more the segmentation accuracy for instance segmentation. Finally, combining semantic and instance segmentation results leads to the optimal result for the initial training dataset. If the final accuracy is not satisfactory, images should be processed by manually correcting the combination of semantic and instance segmentations to increase the size of the training dataset and repeat this operation until an accuracy threshold is met.\n\n\nData availability\n\nThe five annotated images are available at https://github.com/tpecot/DeepLearningBasedSegmentationForBiologists/tree/main/Data/AnnotatedNuclei. This project contains the following data:\n\nPolyp12_[10837,39273]_component_data.tiff: image used for training U-Net and Mask R-CNN in all figures and for training pix2pix in Figure 2\n\nPolyp40_[13694,34105] _component_data.tiff and Polyp42_[12011,37598] _component_data.tiff: two images used for training U-Net and Mask R-CNN in Figure 3\n\nPolyp12_[12699,39273] _component_data.tiff and Polyp42_[12942,36900] _component_data.tiff: two images used for evaluation in all figures\n\nThe images generated with pix2pix and used for training U-Net and Mask R-CNN in Figure 2–Figure 3 are available at https://github.com/tpecot/NucleiSimulationWithConditionalGAN/tree/main/datasets/Nuclei_polyps_1image.\n\n\nSoftware availability\n\nThe code with the parameters used to train and process all experiments presented in this manuscript with U-Net and Mask R-CNN is available at https://github.com/tpecot/DeepLearningBasedSegmentationForBiologists/tree/main/Codes.\n\nArchived code as at time of publication: https://doi.org/10.5281/zenodo.460879533\n\nLicense: GPL3\n\nThe code with the parameters used to train and generate images with pix2pix is available at https://github.com/tpecot/NucleiSimulationWithConditionalGAN.\n\nArchived code as at time of publication: https://doi.org/10.5281/zenodo.460879334\n\nLicense: GPL3\n\nThe ImageJ macro used to convert the output classes obtained with U-Net to individual nuclei is available at https://github.com/tpecot/DeepLearningBasedSegmentationForBiologists/tree/main/Codes/ImageJMacros.\n\nArchived macro as at time of publication: https://doi.org/10.5281/zenodo.460879533\n\nLicense: GPL3",
"appendix": "Acknowledgements\n\nThis publication was supported by COST Action NEU-BIAS (CA15124), funded by COST (European Cooperation in Science and Technology). We acknowledge the Translational Science Lab at the Medical University of South Carolina for help and advice with microscopy.\n\n\nReferences\n\nKrizhevsky A, Sutskever I, Hinton GE: Imagenet classification with deep convolutional neural networks. Adv Neural Inf Process Syst. 2012; 1097–1105. Reference Source\n\nCireşan D, Meier U, Schmidhuber J: Multi-column deep neural networks for image classification. In 2012 IEEE conference on computer vision and pattern recognition. IEEE, 2012; 3642–3649. Publisher Full Text\n\nLeCun Y, Bengio Y, Hinton G: Deep learning. Nature. 2015; 521(7553): 436–444. PubMed Abstract | Publisher Full Text\n\nSchmidhuber J: Deep learning in neural networks: An overview. Neural Netw. 2015; 61: 85–117. PubMed Abstract | Publisher Full Text\n\nHollandi R, Szkalisity A, Toth T, et al.: nucleaizer: a parameter-free deep learning framework for nucleus segmentation using image style transfer. Cell Systems. 2020; 10(5): 453–458.e6. Publisher Full Text\n\nMoen E, Bannon D, Kudo T, et al.: Deep learning for cellular image analysis. Nat Methods. 2019; 16(12): 1233–1246. PubMed Abstract | Publisher Full Text\n\nSchmidt U, Weigert M, Broaddus C, et al.: Cell detection with star-convex polygons. In International Conference on Medical Image Computing and Computer-Assisted Intervention. Springer, 2018; 265–273. Publisher Full Text\n\nMandal S, Uhlmann V: Splinedist: Automated cell segmentation with spline curves. bioRxiv. 2020. Publisher Full Text\n\nLjosa V, Sokolnicki KL, Carpenter AE: Annotated high-throughput microscopy image sets for validation. Nat Methods. 2012; 9(7): 637. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCaicedo JC, Goodman A, Karhohs KW, et al.: Nucleus segmentation across imaging experiments: the 2018 data science bowl. Nat Methods. 2019; 16(12): 1247–1253. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCaicedo JC, Roth J, Goodman A, et al.: Evaluation of deep learning strategies for nucleus segmentation in fluorescence images. Cytometry A. 2019; 95(9): 952–965. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPécot T, Cuitiño MC, Johnson RH, et al.: Deep learning tools and modeling to estimate the temporal expression of E2Fs over the cell cycle from 2D still images. bioRxiv. 2021. Publisher Full Text\n\nIsola P, Zhu JY, Zhou T, et al.: Image-to-image translation with conditional adversarial networks. In Proceedings of the IEEE conference on computer vision and pattern recognition. 2017; 1125–1134. Publisher Full Text\n\nRonneberger O, Fischer P, Brox T: U-Net: Convolutional Networks for Biomedical Image Segmentation. In International Conference on Medical image computing and computer-assisted intervention. Springer, 2015; 234–241. Publisher Full Text\n\nFalk T, Mai D, Bensch R, et al.: U-net: deep learning for cell counting, detection, and morphometry. Nat Methods. 2019; 16(1): 67–70. PubMed Abstract | Publisher Full Text\n\nHe K, Gkioxari G, Dollár P, et al.: Mask r-cnn. In Proceedings of the IEEE international conference on computer vision. 2017; 2961–2969. Reference Source\n\nvan der Walt S, Colbert SC, Varoquaux G: The numpy array: a structure for efficient numerical computation. Computing in Science & Engineering. 2011; 13(2): 22–30. Publisher Full Text\n\nAbadi M, Agarwal A, Barham P, et al.: TensorFlow: Large-Scale Machine Learning on Heterogeneous Distributed Systems. 2015. Reference Source\n\nChollet F: Keras. 2015. Reference Source\n\nVirtanen P, Gommers R, Oliphant TE, et al.: SciPy 1.0: Fundamental Algorithms for Scientific Computing in Python. Nat Methods. 2020: 17(3): 261–272. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan der Walt S, Schönberger JL, Nunez-Iglesias J, et al.: scikit-image: image processing in python. PeerJ. 2014; 2: e453. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVan Valen DA, Kudo T, Lane KM, et al.: Deep learning automates the quantitative analysis of individual cells in live-cell imaging experiments. PLoS Comput Biol. 2016; 12(11): e1005177. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJung AB, Wada K, Crall J, et al.: imgaug. 2020; accessed 01-Feb-2020. Reference Source\n\nSchneider CA, Rasband WS, Eliceiri KW: Nih image to imagej: 25 years of image analysis. Nat Methods. 2012; 9(7): 671–675. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchindelin J, Arganda-Carreras I, Frise E, et al.: Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7): 676–682. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOllion J, Cochennec J, Loll F, et al.: Tango: a generic tool for high-throughput 3d image analysis for studying nuclear organization. Bioinformatics. 2013; 29(14): 1840–1841. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLegland D, Arganda-Carreras I, Andrey P: Morpholibj: integrated library and plugins for mathematical morphology with imagej. Bioinformatics. 2016; 32(22): 3532–3534. PubMed Abstract | Publisher Full Text\n\nHe K, Zhang X, Ren S, et al.: Deep residual learning for image recognition. In Proceedings of the IEEE conference on computer vision and pattern recognition. 2016; 770–778. Publisher Full Text\n\nLin TY, Maire M, Belongie S, et al.: Microsoft coco: Common objects in context. In European conference on computer vision. Springer, 2014; 8693: 740–755. Publisher Full Text\n\nBankhead P, Loughrey MB, Fernández JA, et al.: Qupath: Open source software for digital pathology image analysis. Sci Rep. 2017; 7(1): 16878. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSofroniew N, Lambert T, Evans K, et al.: napari. 2021. Publisher Full Text\n\nVincent L, Soille P: Watersheds in digital spaces: an efficient algorithm based on immersion simulations. IEEE Trans Pattern Anal Mach Intell. 1991; 13(6): 583–598. Publisher Full Text\n\nPécot T: Deep Learning-based segmentation for biologists. 2021. http://www.doi.org/10.5281/zenodo.4608795\n\nPécot T: Nuclei Simulation with Conditional GAN. 2021. http://www.doi.org/10.5281/zenodo.4608793"
}
|
[
{
"id": "89422",
"date": "03 Aug 2021",
"name": "Alice Lucas",
"expertise": [
"Reviewer Expertise Deep Learning",
"Computer Vision",
"Image and Video 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 authors propose multiple strategies to improve segmentation results given a new dataset.\nInstead of manually annotating a training image from scratch, the authors recommend to leverage knowledge learned by networks pre-trained on other larger datasets. Therefore, they propose to first train a model on large existing datasets (that differ from the final dataset of interest). The trained model is then used to annotate the desired training image, and these predictions are then manually corrected using Annotater. This allows the authors to manually annotate for 15-20 hours, compared with 30 hours when annotating the image from scratch.\nA second solution that they implement in order to improve their final segmentation results is to (1) train a conditional GAN on their annotated image and (2) use the cGAN to predict additional synthesized segmentation masks. The UNet and Mask-RCNN can then use this additional data for training.\nFinally, to further improve their results, they combine results obtained from their trained UNet and their trained Mask-RCNN to obtain a final instance segmentation map. More specifically, the semantic segmentations from UNet are post-processed to obtain instance segmentation masks, and merged (following a specific protocol) with those predicted by the trained Mask-RCNN.\nA few comments:\n\nClarity regarding the purposes of the different training sets used could be improved. At first it was not clear to me how the CC/MIE datasets related to the final training dataset of interest (the 1868 x 1400 image). It could be made a bit more explicit that (1) the CC / MIE data is used to pre-train a neural network, (2) this neural network is then applied on the image of interest to provide the annotations, and (3) final training data is obtained by correcting these predictions. (4) On this final training data will be trained UNet and Mask-RCNN.\n\nThe text “Only one image was used to train […]” is a bit of a misleading statement. In the end, when looking at the whole pipeline, a very large dataset of annotated images was used to get to these results.\n\nIt would be interesting to know how many hours it took to pre-train Mask-RCNN and UNet on the large datasets, as well as for training the conditional GAN. This is helpful especially for better comparing the 30 hours of manual annotation from scratch vs. the 15-20 hours when using these strategies.\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? Yes",
"responses": [
{
"c_id": "7594",
"date": "17 Jan 2022",
"name": "Thierry Pecot",
"role": "Author Response",
"response": "We thank Alice Lucas for her insightful remarks and apologize for the delay between her review and our response, we were waiting for a second reviewer. To answer Dr Lucas comments, we changed the manuscript accordingly: We rephrased the first section to better explain what was done. More specifically, U-Net and Mask R-CNN are trained with CC/MIE datasets along with a massive data augmentation. The trained models are then used to segment the image shown in Fig.1 a. The accuracy obtained with these models is compared to the watershed approach and to a Stardist model trained with the 2018 Data Science Bowl. As Mask R-CNN demonstrates the most accurate results, the segmented nuclei obtained with this approach are then manually corrected to initialize a training dataset. To clarify the misleading text “Only one image was used to train […]” , we changed the Training dataset section in Methods and added that publicly available datasets were used in addition to the manually annotated image of human precancerous polyp biopsy. We added a sentence about the time taken to train a Mask R-CNN model on the CC/MIE datasets at the end of the first section to better compare the 30 hours of manual annotation from scratch vs. the 15-20 hours when using this strategy."
}
]
},
{
"id": "101244",
"date": "14 Dec 2021",
"name": "Romain F Laine",
"expertise": [
"Reviewer Expertise I am a quantitative imaging specialist",
"focused on fluorescence microscopy",
"super-resolution",
"and quantitative analysis method development",
"including deep learning."
],
"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\nPecot et al present a nice set of ideas about how to improve the pipeline of nuclei segmentation. The premise of this work is that it is time consuming to generate good quality annotation for DL training. The authors are absolutely right here, it takes time and can be discouraging.\nThe authors test a couple of interesting approaches to help with that:\nUse of large openly accessible dataset to create pretrained dataset, as is commonly done in the field.\n\nUse of data augmentation to improve generalization of the model, also commonly done in the field already.\n\nThe use of a generator model (here pix2pix as a conditional GAN), to expand the size f the training dataset.\n\nCombine output of 2 common segmentation networks (U-Net and MaskRCNN) to improve accuracy.\nThe points 1 and 2 are already well established in the field and will be systematically done nowadays, with almost any DL networks when data is available. Segmentation dataset are available as the authors highlight. So these aspects are sanity checks here and not novel implementations. However, it is reassuring to see that augmentation and use of pretrained models are helpful here as well.\nThe more interesting aspects of this work lie in the use of GAN for expanding the size of the training dataset from an annotated image and the combination of output. Although the use of GAN makes sense for this application, the gains from such approach are clearly quite marginal as can be seen on Figure 2a and 2b comparing the black and red lines, while the main gains are again from the use of additional dataset and augmentation as observed on Figure 1. It's an important observation but maybe not as essential to the pipeline as is described in the manuscript as it stands. I suggest toning down the importance of this and clearly highlighting that the gains are in fact low here. Maybe the authors could further discuss why the gains are only small here: maybe the simulation pipeline from the masks to generate the training dataset of pix2pix is too simplistic for instance, wider range of shapes, background lights, heterogeneity of intensities or patterns on the nuclei etc.\nOn the contrary it's quite clear that the combination of U-Net and MaskRCNN output are beneficial to the overall performance of the method and that's nicely shown here. I think that combining DL model outputs is currently underused and this is a nice additional demonstration of this here.\nAs additional comments, I would highlight a couple of additional work that are missing from the context described in this paper:\nKaibu (Wei Ouyang et al F1000, https://f1000research.com/articles/10-142) is an interactive tool for simultaneous training of segmentation models and segmentation, this circumvents a range of issues mentioned here, it should be mentioned.\n\nStarDist (https://github.com/stardist/stardist) from Uwe Schmidt and Martin Weigert, is an excellent tool for nuclei segmentation and is not included here. I suggest that the authors compare their IoU curves to those obtained from the pre-trained models provided by the method (even as Fiji plugin). This will give the readers a baseline on which to compare the approaches described here, which still require an investment in time to train multiple models and annotations\n\nThe cost/benefit analysis of manual annotation vs automated (DL based or not) should be mentioned, it's not always worth doing DL for that, it often depends on the size of the dataset to be segmented.\n\nAlthough having an annotator GUI and some tools to get some improvement on segmentation performance are important today, a large efforts is now put into approaches that are self-supervised or partially supervised, which would circumvent the issues of annotation time altogether. These are not currently available to the wide bioimaging community but should be mentioned in conclusion, looking at the future of segmentation pipelines.\nOverall, I think that it is a nice piece of work describing the performance of a range of approaches in a systematic and clear manner, which are useful to the bioimaging community. However, they are presented as guidelines to building a segmentation pipeline and I would not think that as such, it describes the general thoughts about the matter in the community. I'd consider rewording the conclusions focusing on the observations of the tests the authors made rather than presenting it as a universal guideline.\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": "7595",
"date": "17 Jan 2022",
"name": "Thierry Pecot",
"role": "Author Response",
"response": "We thank Romain Laine for his enlightening observations. To answer Dr Laine remarks, we changed the manuscript accordingly: We added a sentence about the cost/benefit analysis of manual annotation vs automated in the introduction. We mentioned the use of interactive machine learning and cited Kaibu (Wei Ouyang et al F1000, https://f1000research.com/articles/10-142) at the beginning of the first section. We added a comparison to Stardist trained with the 2018 Science Bowl (Fiji plugin) in Fig.1. We then compared its performance to the watershed approach, to U-Net and to Mask R-CNN trained with the CC/MIE datasets in the first section. We completely changed the discussion, focusing on the observations made in the manuscript. More particularly, we acknowledge that the use of publicly available datasets and massive data augmentation are beneficial to build a training dataset and are now common practices in the field. We also underline the disappointing accuracy obtained when using pix2pix (we also changed the end of section 2 accordingly). We emphasize the interest of combining instance and semantic segmentations. We finally introduce self- and partially supervised methods that offer the promise to eliminate manual annotation."
}
]
}
] | 1
|
https://f1000research.com/articles/10-256
|
https://f1000research.com/articles/11-49/v1
|
17 Jan 22
|
{
"type": "Research Article",
"title": "Clinical inflammatory biomarkers associated with the tumor stage of gastric cancer: retrospective analysis of a Hospital in Peru during the years 2018–2020",
"authors": [
"Jose M. Vela-Ruiz",
"Katherine Medina-Rojas",
"Andrea Machón-Cosme",
"Carlos Perez-Ramos",
"Miguel J. Sotelo",
"Jhony A. De La Cruz-Vargas",
"Katherine Medina-Rojas",
"Andrea Machón-Cosme",
"Carlos Perez-Ramos",
"Miguel J. Sotelo",
"Jhony A. De La Cruz-Vargas"
],
"abstract": "Introduction: Gastric cancer is a disease with a high rate of morbidity and mortality in the world. Objective: To determine which clinical inflammatory biomarkers are associated with the tumor stage of gastric cancer of the oncology service of the Hospital María Auxiliadora in Lima, Peru, during the years 2018-2020. Methodology: Observational, analytical, cross-sectional and retrospective study. There was a sample of 110 patients. The PR values were obtained from the absolute frequencies of the variables: serum albumin, Platelet-Lymphocyte Ratio (PLR) and Neutrophil-Lymphocyte Ratio (NLR). Results: The average age was 63,727±13.85. 55.45% were female. The most frequent histopathological type was intestinal adenocarcinoma with 62.73%. In the bivariate analysis, an association was found between INL (PR:6.88 CI95% 2.36-20 p<0.001), IPL (PR:2.55 CI95% 1.68-3.86 p<0.001) and serum albumin (PR:3.16 CI95% 1.91-5.24 p<0.001) in the advanced clinical stage. The multivariate analysis found a relationship between INL and clinical stage (PR:4.11 CI95% 1.25-13.49 p=0.020) Conclusion: INL is an independent predictive factor in relation to the clinical stage of gastric cancer in this study.",
"keywords": [
"Gastric Cancer",
"Neutrophil-Lymphocyte Ratio",
"Platelet-Lymphocyte Ratio",
"Serum Albumin",
"Tumor Stage (MeSH)"
],
"content": "Introduction\n\nGastric cancer occupies fifth place among commonly diagnosed neoplasms and third place in mortality worldwide.1–3 Stomach cancer has important geographical, ethnic, and socioeconomic differences. Although risk factors are described, the main factors are environmental (Helicobacter pylori, diet, overweight, and obesity) as well as due to host (genetic factors).4\n\nAccording to Globocan, during 2018, in Peru, 5731 new cases of gastric neoplasm were diagnosed, falling in third place of frequency, just below breast and prostate cancer. Furthermore, 4606 of deaths were registered, placing it in first place for mortality.5\n\nThe prognostic molecular, genomic factors and other high complex instruments are currently not available in all hospital centers in economically emerging countries. For this reason, this study seeks to determine the clinical factors associated with tumor stage in gastric cancer that are of easy access and low cost, in order for them to help us identify survival and an adequate treatment.\n\nThe inflammation caused by tumors can promote the tumoral growth, invasion, angiogenesis, and even metastasis. This is why inflammatory markers, such as neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) have shown to be useful in multiple neoplasms.6,7\n\nFurthermore, the systemic inflammatory response induced by tumors may exacerbate malnutrition in patients. Which may promote tumor progression.6 For this reason, albumin has also been considered as an independent prognostic factor for many malignant diseases,8 since low levels of albumin in plasma reflect a chronic inflammation.9\n\nSome researchers have reported that inflammatory markers such as, PLR, and serum albumin may be useful in the prognosis of patients diagnosed with gastric cancer.7,10–12 However, this is still in dispute.\n\nTherefore, our objective was to determine the clinical-inflammatory factors associated with tumor stage of gastric cancer of the oncology service of Hospital María Auxiliadora during the years 2018–2020.\n\n\nMethods\n\nThe research design is an observational, analytical and cross-sectional study.\n\nIt was carried out in male and female patients treated in the oncology service of Hospital María Auxiliadora, Lima, Peru, during the years 2018 to 2020. Inclusion criteria were all patients ≥18 years who had at least a hemoglobin and serum albumin test at the moment of diagnosis of gastric cancer. Exclusion criteria were patients with diagnosis of cancer of the gastroesophageal junction or another diagnosis (gastric lymphoma and others), clinical records that don’t have pathological report by biopsy of gastric cancer or incomplete clinical histories.\n\nA simple random probability sampling of patients was carried out with a population size of 166 patients, and a confidence Interval of 95% and error of 0.05, and a final sample of 110 patients, data was obtained with power size at 90%.\n\nThe sample size calculation was carried out with an NLR risk in exposed of 83% and risk in not exposed of 51%; according to the study published by Huaman et al.10\n\nThe data obtained from the clinical factors associated with tumor stage in patients with gastric cancer were collected using the data collection form approved by the Institute of Biomedical Sciences of the Universidad Ricardo Palma and the Ethics committee of the University, which consisted of four parts:\n\n• Identification: Medical record number, age, sex, weight, height, body mass index (BMI)\n\n• Clinical stage of gastric adenocarcinoma: criterion T, criterion N, criterion M\n\n• NLR/PLR: number of neutrophils, number of platelets, number of lymphocytes\n\n• Serum albumin\n\nThe database continued to be filled in until the expected sample size was completed, checking in detail if there were incomplete data, poorly filled in, or any other cause that could have affected and altered their integrity. Subsequently, there was a review by the Institute's medical advisers and finally they were analyzed (see Figure 1).\n\nTo avoid selection bias: all patients included were confirmed with a diagnosis of gastric cancer according to a pathological report by a biopsy. To avoid information bias, all the laboratory studies (hematological and biochemical) of the patients were carried out in the same hospital laboratory under the instruments, same calibration techniques, reference values and international and national standards according to the guidelines of the Ministry of Health of Peru for a level III Health Hospital with the purpose of obtaining an exhaustive selection of biomarkers according to the objectives of the present study.\n\nThe quantitative variables were NLR, PLR and serum albumin. The quantitative variable of discrete reason was age. The ordinal quantitative variable was BMI. The qualitative variables were the criteria T, N, M and the clinical stage.\n\nThe dependent variable was the tumor clinical stage according to TNM for gastric cancer, for further analysis they were grouped into localized (stage I–II) and advanced (III–IV), the independent variables were the NLR, PLR, and serum albumin, whose cut-off points for NLR and albumin were 2.44 and 3.5, respectively, taking into account the studies by Sun et al.,7 Huamán et al.11 and Lian et al.13; while, for PLR the cut-off point was 284.4 according to the study by Hirahara et al.6 in China, which allows us to classify into high and low values. Possible confounding variables are sex, age and district of origin (sociodemographic variables).\n\nA clinical and laboratory data collection sheet previously mentioned was used as the instrument to collect data from medical record.\n\nData were analyzed using STATA version 14 (RRID:SCR_012763) and SPSS version 22 (RRID:SCR_019096) programs.\n\nIn descriptive statistics, the quantitative variables were presented in measures of central tendency (mean or median) and dispersion measures (standard deviation or interquartile range) prior evaluation of distribution of values. Bar graphs were used for qualitative variables and box and whisker plots were used for quantitative variables.\n\nFor inferential statistics, we worked with 95% confidence with a statistical significance of p < 0.05. The Chi-squared and Poisson statistic tests were used for the analysis of categorical variables. The numeric variables were analyzed with a Student’s t-test (parametric distribution data). The PR values (prevalence ratio) were obtained from absolute frequencies of clinical stage, NLR, PLR and serum albumin variables.\n\nThis study was approved by the Research and Ethics Committee of the Human Medicine Faculty of the Universidad Ricardo Palma, Lima-Peru, with committee code PG-54-2020 on November 13th, 2020.\n\nAll procedures performed in this study preserved fundamental rights and the integrity of patients who were research subjects, guaranteeing the confidentiality of the obtained data.\n\nThis investigation was developed within the context of the VII thesis dissertations, according to the previously published methodology14 and based on the thesis “Clinical factors associated to tumor stage of gastric cancer of the oncology service of Hospital María Auxiliadora during the years 2018-2020”.15\n\n\nResults\n\nIn the Office of Statistics and Informatics, the numbers of the medical records of patients diagnosed with gastric cancer among the years 2018-2020 were 166, 15 had other diagnoses, 9 were duplicate medical records, 17 without pathological report and 15 incomplete histories that did not meet the inclusion criteria. 110 medical records met the inclusion and exclusion criteria for statistical analysis and results (see Figure 1).\n\nThe percentage of patients who were female was 55.45%. The average age in the study was 53 years (range 27–96 years). Furthermore, we can observe that the most frequent histological type of gastric cancer was the intestinal type 62.72% (Table 1). The frequency of signet-ring cell adenocarcinoma was 34.5%.\n\nRegarding the TNM classification and clinical stage, in Figure 2, we demonstrate that 81.8% had a tumoral size criteria of T3–4 at the time of cancer staging. Likewise, 72.7% presented positive lymph nodes and 25.5% presented metastasis. Finally, 77% presented an advanced clinical stage (EC III–IV).\n\nIn Figure 3, we observe the value distribution of NLR, PLR, and serum albumin according to clinical stage. As far as NLR, in the early clinical stage (I–II), the average was 2.75, and in advanced clinical stage the average obtained was 9.50. With respect to PLR, in the early clinical stage (I–II), the average was 168.52, while in the advanced clinical stage (III–IV) the average was 409.93. Lastly, regarding serum albumin, in the early clinical stage (I–II), the average was 3.7, while in advanced clinical stages (III–IV), the average was 3.1. These measures were evaluated with the Student’s t-test, where a significant difference was shown (p < 0.001).\n\nIn the bivariate analysis, patients with NLR greater than 2.44 were approximately 6-times more likely to have the presence of advanced gastric cancer (III–IV), compared with those with NLR lower than 2.44. Likewise, patients with PLR greater than 2448.4 were 2.5-times more likely to have a neoplasm of advanced stage (III–IV) than those with PLR lower than 248.4, and finally, those with albumin values <3.5 were 3-times more present in advanced stages compared with those with normal values. All these results were statistically significant (p < 0.001) (see Table 2). We did not find a statistically significant association regarding age and sex.\n\nIn Table 3, in the multivariate analysis of clinical factors associated to tumor stage of gastric cancer, we observed that patients with NLR greater than 2.44 were 4.11-times more likely to have prevalence of gastric cancer in advanced clinical stage compared with those who had NLR less than 2.44. This result is statistically significant (p < 0.05). PLR and albumin were not statistically significant.\n\n\nDiscussion\n\nGastric cancer is associated with a high morbidity and mortality rate in Peru and worldwide,5 which is why an adequate assessment that allows us to establish a prognosis and make correct therapeutic decisions is necessary.\n\nWithin the immunologic and pathogenic process, gastric cancer is growing in areas of elevated inflammation, involving platelets, neutrophils, and lymphocytes. The inflammatory markers can be used as a tool for the prognosis of said neoplasm.13\n\nIn our research work, we evidenced a greater frequency in those over 50 years of age, which is consistent with the international literature previously reported.16\n\nThe distribution of patients in our research was predominantly female at 55.4%, this result coincides with other studies,7 unlike other studies carried out in other contexts.16,17\n\nWith respect to pathological anatomy, the most frequent type of cancer based on the WHO classification18 was intestinal adenocarcinoma at 62.72% (tubular adenocarcinoma: 60.9% and papillary adenocarcinoma: 1.82%) and in second place was diffuse adenocarcinoma with 37.28% (with signet-ring cells: 36.37% and mucinous adenocarcinoma: 0.91%), results were similar to those already intentionally reported and mentioned by Reyes19 and Ramírez et al.,20 where intestinal type gastric adenocarcinoma versus diffuse was 68.3% versus 31.7% and 63.8% versus 25%, respectively.\n\nRegarding clinical stage, we evidenced that 70% were in advanced stages (III–IV), while 30% corresponded to early stages (I–II). Similar to a study in Peru in 2019, reporting 70.8% in advanced stage (III–IV) and 29.2% were in early stages (I–II),11 confirming a diagnosis in late stages among the Peruvian population in both studies, as was mentioned in previous studies.13\n\nIn the bivariate analysis report, we evidenced that patients with a NLR greater than 2.44 were 6.88-times more prevalent to have gastric cancer in advanced clinical stage. This coincides with a study carried out by Jingxu Sun et al.7 where it was evidenced that NLR was greater in patients with gastric cancer in advanced stages compared with gastric cancer in early stages (OR: 2.76; 95% CI: 0.85–3.54; p < 0.005). Along the same lines, Zhang et al.21 in 2018, found that those who had NLR lower were in early clinical stages (p < 0.001). These findings suggest that NLR values are useful as predictive factors in advanced tumoral stages.\n\nRegarding PLR, withing the bivariate analysis we evidenced that patients with values greater than 248.4 were 2.55-times more prevalent to have gastric cancer in advanced clinical stages. These findings were similar to those observed in the study carried out by Lian et al.,13 where high levels of PLR were associated with advanced stages of the tumor, metastasis to lymph nodes and a greater depth of tumor invasion (p < 0,005). In the same manner, Zhang et al. found that patients with high PLR had 1.17- and 1.99-times the risk of having an advanced clinical stage, respectively.21,22\n\nWe found that low serum albumin increased the prevalence of having a late clinical stage by 3.16-times. These results coincide with that reported by Huamán et al.,11 who evidenced that low serum albumin is a predictive factor for gastric cancer in advanced tumor stage (OR: 13.02 95% CI 1.78–5.36; p < 0.005).\n\nIn the multivariate analysis report, we observed that patients with a NLR greater than 2.44- had 4.11-times the prevalence of having advanced clinical stage gastric cancer (p < 0.02). Regarding PLR and albumin level, they did not reach a statistically significant relationship. These results suggest that NLR is a potentially independent predictive factor of gastric cancer in advanced clinical stage. These findings are supported by the retrospective cohort study carried out by Zhao et al.,23 who found an association with NLR (HR: 1.61; CI 95%: 1.032–2.525; p = 0.036) in the multivariate and by the retrospective longitudinal study published by Ramos-Esquivel et al.,24 where, in the multivariate, only the NLR was associated independently to a poor global survival (HR: 1.59; 95%CI: 1.15–2.28; p = 0.005).\n\nWhile this study has limitations, such as being an observational, retrospective and unicentric study with a limited number of patients, however, poor global survival, the study population is representative of a referral hospital in the south of Lima, Peru with a statistical power greater than 90%. Furthermore, these inflammatory biomarkers are of easy access, economical and reproducible, with a potentially prognostic use in the clinical medical practice. Multicentric, prospective studies are necessary to confirm these results.\n\n\nConclusions\n\nThe inflammatory markers (NLR and PLR) and hypoalbuminemia were associated to advanced gastric cancer clinical stage by bivariate analysis. NLR resulted as an independent predictive factor in relation to the clinical stage of gastric cancer in this study.\n\nZenodo: Underlying data for ‘Clinical inflammatory biomarkers associated with the tumor stage of gastric cancer: retrospective analysis of a Hospital in Peru during the years 2018–2020’ https://doi.org/10.5281/zenodo.5781815\n\nThe project contains the following data:\n\n• GASTRIC CANCER DATASET, HOSPITAL MARIA AUXILIADORA, LIMA, PERU, 2018-2020. (main data)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)",
"appendix": "Acknowledgments\n\nWe thank the Instituto de Investigaciones en Ciencias Biomédicas de la Universidad Ricardo Palma, the team and staff of admissions/statistics/archives: Miguel Chutas from Hospital María Auxiliadora and the research unit from the Oncology department of Hospital María Auxiliadora.\n\n\nReferences\n\nOn On Chan A, Wong B: Epidemiology of gastric cancer - UpToDate.2020 [cited on October 1, 2020]. Reference Source\n\nMariuska MD, Sahilí CA, Miguel VH, et al.: Cáncer gástrico: algunas consideraciones sobre factores de riesgo y Helicobacter pylori. Rev.Med.Electrón. 2018 Abr [cited on June 28, 2021]; 40(2): 433–444. Reference Source\n\nPark JY, Forman D, Waskito LA, et al.: Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins (Basel). 19 de 2018; 10(4). PubMed Abstract | Publisher Full Text\n\nOn On Chan A, Wong B: Risk factors for gastric cancer - UpToDate.2020 [cited on October 1, 2020]. Reference Source\n\nPerú: Souce: GLOBOCAN 2018. Global Cancer Observatory.2019. [cited on October 1, 2020]. Reference Source\n\nHirahara T, Arigami T, Yanagita S, et al.: Combined neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts chemotherapy response and prognosis in patients with advanced gastric cancer. BMC Cancer. 8 de julio de 2019 [cited on October 14, 2020]; 19: 672. PubMed Abstract | Publisher Full Text\n\nSun J, Chen X, Gao P, et al.: Can the Neutrophil to Lymphocyte Ratio Be Used to Determine Gastric Cancer Treatment Outcomes? A Systematic Review and Meta-Analysis. Dis. Markers. 2016 [cited on September 30, 2020]; 2016: 1–10. PubMed Abstract | Publisher Full Text\n\nZu H, Wang H, Li C, et al.: Preoperative prealbumin levels on admission as an independent predictive factor in patients with gastric cancer. Medicine. marzo de 2020 [cited on October 11,2020]; 99(11): e19196. PubMed Abstract | Publisher Full Text\n\nMao M, Wei X, Sheng H, et al.: Clinical Significance of Preoperative Albumin and Globulin Ratio in Patients with Gastric Cancer Undergoing Treatment. Biomed. Res. Int. 2017 [cited on October 11, 2020]; 2017: 1–8. PubMed Abstract | Publisher Full Text\n\nHuaman-García M, Cerna-Barco J, Correa-López LE, et al.: Albumina e índice neutrófilo-linfocito como predictores de estadío tumoral en pacientes con cáncer gástrico. Revista de la Facultad de Medicina Humana. 18 de septiembre de 2020; 20(2): 96–113. Publisher Full Text Reference Source\n\nHuamán M: Factores clinico patologicos asociados al estadio tumoral en pacientes con diagnostico de cancer gastrico en el servicio de cirugia de estomago del HNERM durante los años 2017-2018. [Perú]: Universidad Ricardo Palma; 2019.\n\nZhang Y, Lu J-J, Du Y-P, et al.: Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in gastric cancer. Medicine (Baltimore). 23 de marzo de 2018 [cited on October 14, 2020]; 97(12): e0144. PubMed Abstract | Publisher Full Text\n\nLian L, Xia Y-Y, Zhou C, et al.: Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer. Cancer Biomarkers: Section A of Disease Markers. 2015; 15(6): 899–907. PubMed Abstract | Publisher Full Text\n\nDe La Cruz-Vargas JA, Correa-Lopez LE, Alatrista-Gutierrez de Bambaren MdS, et al.: Promoviendo la investigación en estudiantes de Medicina y elevando la producción científica en las universidades: experiencia del Curso Taller de Titulación por Tesis. Educación Médica. 1 de julio de 2019; 20(4): 199–205. Publisher Full Text\n\nMachón Cosme A, Medina Rojas KN: Factores clínicos asociados al estadio tumoral de cáncer gástrico del servicio de oncología del hospital maría auxiliadora durante los años 2018-2020. Repositorio institucional - URP. 2021 [cited on September 19, 2021]. Reference Source\n\nRondán F: Factores de riesgo asociados al cancer gastrico en pacientes atendidos en el consultorio externo del servicio de gastroenterologia del HNU durante el año 2014. [Perú]: Universidad Ricardo Palma; 2014.\n\nAdriana DM, Fanny QR, Kricia CA, et al.: Caracterización clínica y epidemiológica de la población tamizada en el centro de detección temprana de cáncer gástrico, costa rica: período 1996-2015. Rev. costarric. salud pública. 2018 Dec [cited on June 27, 2021]; 27(2): 68–81. Reference Source\n\nLauwers G, Kumarasinghe P: Gastric cancer: Pathology and molecular pathogenesis - UpToDate.2020 [cited on October 2, 2020]. Reference Source\n\nReyes G: Factores de riesgo y complicaciones del cáncer de estómago en el año 2016. [Ecuador]: Universidad de Guayaquil; 2017.\n\nEduardo CR, Surama GP, Nelson LV, et al.: Cáncer gástrico en pacientes atendidos en servicio de endoscopia digestiva. Rev Ciencias Médicas. 2017 Oct [cited on June 28, 2021]; 21(5): 46–53. Reference Source\n\nZhang L, Wei Z, Xu A, et al.: Can the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio be beneficial in predicting lymph node metastasis and promising prognostic markers of gastric cancer patients? Tumor maker retrospective study. Int. J. Surg. 1 de agosto de 2018; 56: 320–327. Publisher Full Text\n\nZhang X, Zhao W, Yu Y, et al.: Clinicopathological and prognostic significance of platelet-lymphocyte ratio (PLR) in gastric cancer: an updated meta-analysis. World J. Surg. Oncol. 30 de julio de 2020; 18(1): 191. PubMed Abstract | Publisher Full Text\n\nZhao G, Liu N, Wang S, et al.: Prognostic significance of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in patients with metastatic gastric cancer. Medicine (Baltimore). 6 de marzo de 2020 [cited on October 14, 2020]; 99(10): e19405. PubMed Abstract | Publisher Full Text\n\nRamos-Esquivel A, Brenes D, Cordero E, et al.: Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are independent prognostic factors for overall survival in Hispanic patients with gastric adenocarcinoma. Ann. Oncol. junio de 2018; 29: v16. Publisher Full Text"
}
|
[
{
"id": "207083",
"date": "26 Oct 2023",
"name": "Erdogan Selcuk Seber",
"expertise": [
"Reviewer Expertise solid organ malignancies chemotherapy",
"targeted therapy and immunotherapy"
],
"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\nIt is noteworthy that the article was published from a region where stomach cancer is relatively more prevalent.\nHowever, the fact that inflammatory markers, which are nowadays a popular predictive and prognostic parameter, were only used to predict the stage of the disease greatly reduces the scientific value of the data since radiological and pathological investigations can provide accurate staging detail already.\n\nMy recommendation would be for the authors to use the retrospective data they have and turn it into an article investigating the effects of inflammatory markers on the prognosis of patients and this time make an extra effort to include gastric cancer subtypes as a separate investigational parameter.\nAnother important point is that the authors used cutoff values chosen from the literature instead of determining their own cutoffs. However, Peru and China are very different geographical regions and expected to have different etiological factors for gastric cancer and therefore inflammatory markers are expected to have different cut offs.\nAfter determining their own cut off values, it would be much more valuable to make a comparison with other studies in the literature.\nI strongly suggest that the authors rewrite the article with a more comprehensive data analysis.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-49
|
https://f1000research.com/articles/10-1190/v1
|
24 Nov 21
|
{
"type": "Research Article",
"title": "Crowd density estimation using deep learning for Hajj pilgrimage video analytics",
"authors": [
"MD ROMAN BHUIYAN",
"Dr Junaidi Abdullah",
"Dr Noramiza Hashim",
"Fahmid Al Farid",
"Dr Jia Uddin",
"Norra Abdullah",
"Dr Mohd Ali Samsudin",
"Dr Junaidi Abdullah",
"Dr Noramiza Hashim",
"Fahmid Al Farid",
"Dr Jia Uddin",
"Norra Abdullah",
"Dr Mohd Ali Samsudin"
],
"abstract": "Background: This paper focuses on advances in crowd control study with an emphasis on high-density crowds, particularly Hajj crowds. Video analysis and visual surveillance have been of increasing importance in order to enhance the safety and security of pilgrimages in Makkah, Saudi Arabia. Hajj is considered to be a particularly distinctive event, with hundreds of thousands of people gathering in a small space, which does not allow a precise analysis of video footage using advanced video and computer vision algorithms. This paper aims to propose an algorithm based on a Convolutional Neural Networks model specifically for Hajj applications. Additionally, the work introduces a system for counting and then estimating the crowd density. Methods: The model adopts an architecture which detects each person in the crowd, spots head location with a bounding box and does the counting in our own novel dataset (HAJJ-Crowd). Results: Our algorithm outperforms the state-of-the-art method, and attains a remarkable Mean Absolute Error result of 200 (average of 82.0 improvement) and Mean Square Error of 240 (average of 135.54 improvement). Conclusions: In our new HAJJ-Crowd dataset for evaluation and testing, we have a density map and prediction results of some standard methods.",
"keywords": [
"Visual Surveillance",
"Density Estimation",
"Crowd Counting",
"CNN."
],
"content": "Introduction\n\nHajj has been used as an opportunity for certain rituals. The Hajj is linked to the life of the Islamic prophet Muhammad, who lived in the seventh century AD, although Muslims believe that the tradition of pilgrimage to Mecca dates all the way back to Abraham’s time.1 For four to five days a year, over two million pilgrims from several parts of the world come to Mecca, where they tour the many places in Mecca and perform rituals.2 Each ritual has a short but challenging path to take. The Hajj authorities have confirmed that they are having difficulties in monitoring crowd density, which can be seen from the tragedies that occurred in September 2015.3 Regression-based approaches are normally used to estimate crowd density, to infer a mapping between lower-level capabilities and crowd evaluation.1,2\n\nIn this paper, we propose a method for crowd analysis and density estimation using deep learning.2 Our aim is to analyze the map of crowd videos and then use visualization for cross-scene crowd analysis in unseen target scenes. To do this, we must overcome the following obstacles: The challenge of prevailing multitude analysis is insufficient to help in the comparison of research into scene analysis.4–6\n\nThe main contributions of this research include:\n\n1. A methodology to accurately perform the multitude analysis from an arbitrary multitude density and arbitrary perspectives in a separate video.\n\n2. An evaluation of interventions and a comparison of these established methods specifically for activity with recent deep CNN networks.\n\n3. A new dataset based on Hajj pilgrimage specifically for the crowds around the Kaaba area. Crowd datasets such as Shanghai Tech, UCSD, and UCF CC 50 are available for crowd analysis research, however our dataset contains large numbers of crowds.\n\n\nRelated works\n\nEarly works on the usage of detection methods in crowd counting are presented.7–11 Typically, these approaches refer to an individual or head detector through a sliding picture window. Recently, many exceptional object detectors have been presented, including Region Based Convolutional Neural Networks (R-CNN),12–14 YOLO15 and SSD,16 which can have a low precision of detection in scattered scenes. Some works such as Idrees et al.17 and Chan et al.18 implement regression-based approaches that learn directly from the crowd images in order to minimize these issues. They normally extract global19 (texture, gradient, edge) or local characteristics20 for the first step (SIFT,21 LBP,22 HOG,23 and GLCM21). Then several regression techniques such as linear regression24 and Gaussian mixture regression25 are employed to map the crowd counting function. These approaches manage the problems of occlusion and context disorder successfully, but spatial detail is still ignored. Thus, Lemptisky et al.26 have developed a framework that focuses on density assessment, learning to linearly plot local features and charts. A non-linear mapping, random forest regression, which is achieved the same forest to train two separate forests, is proposed in order to reduce the challenge of studying linear mapping.27 Previous heuristic models that traditionally used CNNs to estimate crowd density28–31 have improved significantly compared to conventional handcrafted methods.\n\n\nMethods\n\nWe proposed a model that employs the state-of-the-art crowd counting algorithms used for the Hajj pilgrimage. The algorithms predicted specific regions on people’s heads for Hajj crowd images. The head size for each individual is identified using multi-stage procedures. Figure 1 shows the suggested architecture of CNNs, which is made up of three key components. The first component is the extraction of frames. To do this, we first gathered video clips of Hajj pilgrims. For this experiment we have collected video clips from YouTube using video recording software. To develop this model, we have used programming language python 3.6.15 with others libaries such as/opencv-python 3.4.11.43, NumPy 1.21.2, SciPy 1.21.2 and matplotlib 3.4.3.32 We executed 30 frame extractions per second to assemble all of the footage into one clip. Feature extraction at different resolutions is the method used in spatial feature extraction. The CNN prediction map has been utilized in our proposed method. A set of multi-scale feedback reasoning networks (MSFRN) was used to route the results of mapping to the MSFRN. Results from mapping were sent to the MSFRN where information fused across the scales and predictions were formed using boxes.32 Finally, crowd density results were obtained by utilizing the Non-Maximum Suppression (NMS) which uses several resolutions in combination to arrive at the accurate result. After completing the whole process we got the crowd density result. To compare with our proposed method the following existing algorithms were used. Adversarial Cross-Scale Consistency Pursuit was suggested by Zan Shen et al. as a new paradigm for crowd counting (density estimation) (ACSCP). A three-part Perspective Crowd Counting Network (PCC Net) has been suggested by Junyu Gao et al. Yuhong Li et al. suggested CSRNet made up of two main parts: CNN as the front-end for 2D feature extraction and a dilated CNN as the back-end. The CP-CNN developed by Vishwanath A et al. has four modules: the GCE, the LCE, the DME, and a Fusion-CNN (F-CNN). An image’s change in crowd density may be used to enhance the accuracy and localisation of the projected crowd count, as suggested by Deepak Babu Sam et al.\n\nIn addition to CNN detectors, all existing CNN-related detectors are built on a deep-backbone feature extractor network. Furthermore, it is possible that detection accuracy is linked to functionality consistency. CNN-enabled networks are often used in counting crowds, and give an approximate real time performance.31 The first five CNN convolution blocks initialized using ImageNet training are the backbone network’s starting point.33\n\nInstead of making everything the same size, we used a per pixel categorization approach for scaling. The model classifies each head as part of or inside the context of one of the bounding boxes. Model scale branches generate map set DnshnB=0, showing the confidence level for each pixel for classes of the box. The final requirement for training the model is to know the model’s users’ head sizes, which is not easily accessible and cannot be reliably inputted from typical crowd sourced databases. We created a method to help estimate head sizes in this research. We used the crowd dataset accessible point annotations to get the ground truth. People’s heads are located at certain coordinates with these annotations. Note that only quadratic boxes are regarded as box-like. However, on the whole, they are deemed experimentally effective,\n\nIn choosing the Box U+03B2 (s)/b s for each scale, a popular approach is used. At the maximum resolution scale (s = ns U+2212 1), the initial box size (b = 1) is often set at one, which increases the ability to handle the extremely congested density. The standard size of increase values on different scales are the y = 4, 2, 1, 1 definition. Please note that at high-level (0.5 and 0.25), in which coarse resolution is appropriate (as shown by Figure 1), boxes of better sizes include those of low resolution (0.16 and 0.25).33\n\nFor testing the model in Figure 1, the predictive fusion procedure is utilized in place. The multi-resolution prediction is made across all branches of the picture pipeline. Using these prediction charts, we can anticipate that the locations of the boxes are linearly scaled from the resolution of the input. When the present NMS is in place, then it is used to prevent multi-threshold mixing.\n\nThe HAJJ-crowd dataset was collected from live television broadcasts via YouTube of the Mecca Hajj 2019. All of the images depict pilgrims performing tawaf around the magnificent kaaba. Tawaf involves walking around the Kabba seven times. The moving process begins in the opposite direction of the clock. The video frames have been extracted and saved as.jpg files for future examination. The dataset contains a total of 1500 crowd images. As a result, 1500 images and ten film sequences are captured in several populous areas surrounding Kaaba (Tawaf region), with some typical crowd scenarios, such as touching a black stone in the Kaaba region and tossing a stone into the Mina region. All images have a resolution 1280 × 720 HD and videos have a resolution 1080p.\n\nWe used python 3.6.15 and opencv-python 3.4.11.43 as an annotation tool to easily annotate head positions in the crowds. The process involved two types of labelling: point and bounding box. During the annotation process, the head is freely zoomed in/out, split into a maximum of 3 × 3 tiny patches, allowing annotators to mark a head in 5 sizes: 2x (x = 0,1,2,3,4) times the original image size.\n\nFirstly, we gathered all images of size 1280 × 720 pixels. Then we applied a profound learning method to improve the CNN and obtain the best outcomes. Training and analysis was done using the pytorch 1.9.1 framework and operating system Ubuntu 18.04.6 LTS deep learning packages on NVIDIA GEFORCE GTX 1660Ti GPU. For profound learning, we utilized packages such as opencv-python 3.4.11.43, NumPy 1.21.2, SciPy 1.21.2, matplotlib 3.4.3.\n\nThe HAJJ-crowd data collection consisted of three sections, the examination, validation and training. The count accuracy which is the Mean Absolute Error (MAE) and Mean Squared Error (MSE) should be measured in two measurements. The equations are shown below:\n\nIn this scenario, N is assumed to be the test sample, yi is regarded as the count mark, whereas y′i is the approximation count sample. For each set of persons, the preceding group consists of (0), (0, 1000) (1000, 2000), (2000, 3000). In accordance with the annotated number and quality of the image, each image is allocated an attributing label. In the test set, MAE and MSE are applied for the matching samples in a particular viewpoint for each class. For example, the luminescence attribute calculates average MSE and MAE figures based on two categories that demonstrate the counting models’ sensitivity to luminescence variation.\n\n\nResults analysis\n\nFigure 2(a) and Figure 2(c) indicate clearly that there is no significant change in the loss of pixels from zero to ten epochs, whereas there is a ten pixel loss from ten to 20 epochs. However, the pixel loss between 20 and 30 epochs keeps increasing, up to 40–52 epochs. At the end, the pixel loss is 15.0 at 52 epochs. We may get genuine training loss from this experiment. More than anything, the legitimate pixel loss in tests is 17 at 40 epochs and 14 at 52 epochs. At the same time, based on the preceding equation, we computed the MAE test. We have computed the valid MAE test loss and the valid MAE test that is shown in Figure 2(b) and Figure 2(d). For the MAE test, we found that the error is over 600 when the epoch is zero. We saw the error coming down to 200.0 after 52 epochs. In the Test MSE, we saw the error is over 425 if the epoch is zero. After that, we saw that the error came down to 240.0, after 52 epochs. Figure 2 shows the graphical representations of the results.\n\nMAE = mean absolute error; MSE = mean squared error.\n\nThe HAJJ-crowd dataset contains a large number of crowds as well as a density collection. It contains 1050 training images and 450 testing images with the same resolution of 1280 × 720 pixels. The mainstream UCF CC 50 dataset are compared with the most advanced non-defined approaches34–38 in terms of the MAE and MSE. Our method and dataset outperforms the state-of-the-art methods, and attains a remarkable MAE result of: 200.0 (Average of 82.0 points improvement) and MSE of 240.0 (Average of 135.54 points improvement). Table 1 shows the comparison with state-of-the-art methods.\n\nMAE = mean absolute error; MSE = mean squared error.\n\n\nConclusions\n\nThis paper provides a new approach for crowd density estimation using a convolutional neural network. A multi-column structure of high-level feedback processing that addresses the problems in large crowds is the proposed model of the convolutional neural network. The proposed model can recognize moving crowds, which leads to improved performance. We found that crowd analysis prior to crowd counting has significantly boosted the efficiency of counting for extremely dense crowd scenarios.\n\n\nData availability\n\nDue to the ethical and copyright limitations around social media data, the underlying data for this study cannot be disclosed. The original dataset contains a total of 1500 images, all of which were collected from the Mecca Hajj 2019. The dataset contains three classes of crowd density around tawaf area. The Methods section offers extensive information that will enable the research to be replicated. If you have any questions concerning the approach, please contact the corresponding author.\n\nSoftware available from: https://github.com/romanbhuiyan/CrowdCounting.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.5635486.32\n\nLicense: https://opensource.org/licenses/gpl-licenseGPL.\n\n\nAuthor contributions\n\nR.B. developed the experimental model, structure of the manuscript, performance evaluation and wrote the preliminary draft. J.A. helped to fix the error code, checked the labelled data and results as well as reviewed the full paper. N.H. gave some important feedback on this paper. F.F. helped with the structured full paper revision. J.U. helped format the full paper. N.A. checked the revised version and added a few paragraphs to the full article. M.A.S. helped with the paper organization. All authors discussed the results and contributed to the final manuscript.",
"appendix": "Acknowledgements\n\nMultimedia University, Cyberjaya, Malaysia fully supported this research. The grant number is MMUE/210030.\n\n\nReferences\n\nArmstrong K: Islam: A short history. modern library chronicles (revised updated ed.). Modern Library. 2020; (pp.10–12). 0-8129-6618-X.\n\nAlazbah A, Zafar B: Pilgrimage (hajj) crowd management using agent-based method. International Journal on Foundations of Computer Science & Technology. 2019; 09(1): 01–17. Publisher Full Text\n\nS. and agencies: A history of hajj tragedies.). The Guardian. Jan. 13, 2006. (accessed Aug. 31, 2021).Reference Source\n\nChen K, Gong S, Xiang T, et al.: Cumulative attribute space for age and crowd density estimation. Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. 2013; pages 2467–2474.\n\nChen K, Loy CC, Gong S, et al.: Feature mining for localised crowd counting. 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IEEE; 2008; pages 1–4.\n\nWang L, Lisheng X, Yang M-H: Pedestrian detection in crowded scenes via scale and occlusion analysis. 2016 IEEE International Conference on Image Processing (ICIP). IEEE; 2016; pages 1210–1214.\n\nEnzweiler M, Gavrila DM: Monocular pedestrian detection: Survey and experiments. IEEE Transactions on Pattern Analysis and Machine Intelligence. 2008; 31(12): 2179–2195.\n\nGirshick R: Fast r-cnn. Proceedings of the IEEE International Conference on Computer Vision. 2015; pages 1440–1448.\n\nRen S, He K, Girshick R, et al.: Faster r-cnn: Towards real-time object detection with region proposal networks. Adv. Neural Inf. Process. Syst. 2015; 28: 91–99.\n\nMinghu W, Yue H, Wang J, et al.: Object detection based on rgc mask r-cnn. IET Image Processing. 2020; 14(8): 1502–1508. Publisher Full Text\n\nRedmon J, Divvala S, Girshick R, et al.: You only look once: Unified, real-time object detection. 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Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. 2017; pages 5744–5752.\n\nSindagi VA, Patel VM: Generating high-quality crowd density maps using contextual pyramid cnns. Proceedings of the IEEE International Conference on Computer Vision. 2017; pages 1861–1870.\n\nLi Y, Zhang X, Chen D: Csrnet: Dilated convolutional neural networks for understanding the highly congested scenes. Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. 2018; pages 1091–1100."
}
|
[
{
"id": "101065",
"date": "29 Nov 2021",
"name": "Md Junayed Hasan",
"expertise": [
"Reviewer Expertise Machine Learning",
"Deep Learning",
"Data Science",
"Computer Vision",
"Fault Diagnosis"
],
"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 focuses on recent developments in crowd control research, with a focus on high-density crowds, particularly those attending the Hajj. In order to improve the safety and security of pilgrimages in Makkah, Saudi Arabia, video analysis and visual surveillance have become increasingly important. The Hajj is a unique event in that it brings together hundreds of thousands of people in a limited space, making it difficult to analyze video material using advanced video and computer vision algorithms. The goal of this paper is to present a Hajj-specific method based on a Convolutional Neural Networks model. The work also proposes a method for counting and then estimating crowd density.\nA very unique work indeed. However, few suggestions to the authors.\nThe details of train, test, and validation is not clear from the manuscript. How much data you have actually used to perform this test? Train, test, and Validation – specifically.\n\nPlease mention about the cross-fold validation. How much fold you have used?\n\nHow did you tune your hyperparameters?\n\nFor the result section, why did you only use MSE and MAE. What about Precision, Recall, and F1? Unless the authors include these results, it is not justifiable.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7686",
"date": "14 Jan 2022",
"name": "MD ROMAN BHUIYAN",
"role": "Author Response",
"response": "1. The details of train, test, and validation is not clear from the manuscript. How much data you have actually used to perform this test? Train, test, and Validation – specifically. Ans: For our Hajj-Crowd dataset, we have used 80% data for training and 20% data for testing and we could successfully validate 90% data. 2. Please mention about the cross-fold validation. How much fold you have used? Ans: For our experiment, we have used three fold cross validation. 3. How did you tune your hyper parameters? Ans: We have defined the range of possible values for all hyperparameters and a method for sampling hyperparameter values as well as an evaluative criteria and a cross-validation method. In general, this process includes: Define a model. Define the range of possible values for all hyperparameters. Define a method for sampling hyperparameter values. Define an evaluative criteria to judge the model. Define a cross-validation method. 4. For the result section, why did you only use MSE and MAE. What about Precision, Recall, and F1? Unless the authors include these results, it is not justifiable. Ans: To the best of our knowledge, as we are doing crowd counting here, that is why it is not mandatory to include Precision, Recall, and F1 score."
}
]
},
{
"id": "101069",
"date": "06 Dec 2021",
"name": "Mohamed Uvaze Ahamed",
"expertise": [
"Reviewer Expertise Computer Vision",
"Image Processing and Machine Learning"
],
"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 proposed a model for crowd density estimation using a convolutional neural network. Overall, the article is a clear, concise, and well-written manuscript. Though, the work has been well presented with neat technical flow, there are certain clarifications that need to be addressed by the author.\nThe following comments are the possible doubts/suggestions that need to be worked carefully for the betterment of the overall article:\nIn the Methods section, the authors wrote the following statement:\n“Figure 1 shows the suggested architecture of CNNs, which is made up of three key components”.\nBut actually Figure 1 shows the proposed model. Also, it doesn’t explain the architecture of CNN or DNN.\n\nDue to ethical issues, the authors haven’t supplied the exact dataset. Also, the authors described in Methods section that they have collected the data from YouTube videos. Probably, the authors could provide the video link in the reference, so that the real complexity in the video could be understandable.\n\nAlso author need to clarify the necessity of using MAE and MSE as their performance analysis.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7687",
"date": "14 Jan 2022",
"name": "MD ROMAN BHUIYAN",
"role": "Author Response",
"response": "1. In the Methods section, the authors wrote the following statement: “Figure 1 shows the suggested architecture of CNNs, which is made up of three key components”. But actually Figure 1 shows the proposed model. Also, it doesn’t explain the architecture of CNN or DNN. Ans: Typically, a CNN design consists of a single input layer, many convolutional and pooling layers, numerous fully connected layers, and a final output layer for automating the feature extraction process. As input, an RGB crowd image of 224 by 224 pixels is accepted, with data down sampling in each block for maximum pooling. Except for the last blocks, which are copied by the following blocks, every block on the network branches. A resolution of 0.5, 0.25, 0.125, and 0.166 is utilized to generate feature maps when using cloned blocks. 2. Due to ethical issues, the authors haven’t supplied the exact dataset. Also, the authors described in Methods section that they have collected the data from YouTube videos. Probably, the authors could provide the video link in the reference, so that the real complexity in the video could be understandable. Ans: Ma J: عبدالودود حنيف ماتيسر من سورة يوسف والرعد وإبراهيم. Available at: https://www.youtube.com/watch?v=oxKSe6bFY_E, 2019 (Accessed: 28 December 2021). 3. Also author need to clarify the necessity of using MAE and MSE as their performance analysis. Ans: MSE is calculated as follows, which makes mathematical operations easier than with a non-differentiable function such as MAE. That is why MAE and MSE are very important for the performance analysis in our experiment."
}
]
},
{
"id": "101072",
"date": "20 Dec 2021",
"name": "Saravana Balaji B",
"expertise": [
"Reviewer Expertise Machine Learning",
"Deep Learning",
"Cloud Computing."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe introduction section is brief: highlight the need for density estimation and the current issues in density estimation. Also, emphasize the short note about the proposed method.\nThe related work section should group the works technically and highlight the drawbacks.\nThe classification of heads from the images is not clearly defined mathematically; explain it.\nThe annotation process should be explained clearly: point and bounding box - define them.\nThe abstract should be rewritten, \"This paper aims to propose an algorithm\" - this statement is not correct.\nThe conclusion also does not emphasize the technical solution and the findings, rewrite accordingly.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7688",
"date": "14 Jan 2022",
"name": "MD ROMAN BHUIYAN",
"role": "Author Response",
"response": "1. The introduction section is brief: highlight the need for density estimation and the current issues in density estimation. Also, emphasize the short note about the proposed method. Ans: The benefit of the Convolutional Neural Network (CNN) model is that it is superior than handcrafted features in identifying crowd-specific characteristics. We propose a framework for crowd counting based on convolutional neural networks (CNNs) in this study. 2. The related work section should group the works technically and highlight the draw backs. Ans: Considering the drawbacks of these conventional methods we have employed improved CNN. 3. The classification of heads from the images is not clearly defined mathematically; explain it. Ans: It is situated approximately in the center of the head, though it may vary drastically depending on the number of people. The same applies to scale, since it not only indicates the scale of each person in the crowd, but also shows scale in the form of annotation points. Assuming a homogeneous density of the crowd, the space between two nearby people may represent the size of the box, depending on the dimensions of the crowd. Know that only quadratic boxes are regarded as box-like. In simpler words, a given head size is equivalent to the length of the neighbor closest to it. It is right to use these boxes for crowds of medium to large sizes, but for those with sparse populations with far closest neighbors, these box dimensions may be wrong. However, on the whole, they are deemed experimentally effective, providing an accurate distribution of head sizes throughout a broad range of densities. 4. The annotation process should be explained clearly: point and bounding box - define them. Ans: In this study, we developed a technique for estimating head sizes. To get the ground truth, we utilized available point annotations from the crowd dataset. With these annotations, the heads of individuals are positioned at certain locations. It is worth noting that only quadratic boxes are considered box-like. It is located about in the middle of the head, but this might vary significantly depending on the population. The same holds true for scale, which not only represents the size of each individual in the crowd but also displays scale in the form of annotation points. 5. The abstract should be rewritten, \"This paper aims to propose an algorithm\" - this statement is not correct. Ans: This research proposes an algorithm based on a Convolutional Neural Networks model specifically for Hajj applications. 6. The conclusion also does not emphasize the technical solution and the findings, rewrite accordingly. Ans: The proposed method outperforms the state-of-the-art method, with a Mean Absolute Error of 200 and a Mean Square Error of 240."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1190
|
https://f1000research.com/articles/11-47/v1
|
14 Jan 22
|
{
"type": "Research Article",
"title": "The effect of corporate social responsibility on Malaysian financial institutions' dividend payout",
"authors": [
"Abdullah Sallehhuddin",
"Teo Boon Keong",
"Norzarina Md Yatim",
"Teo Boon Keong",
"Norzarina Md Yatim"
],
"abstract": "Background: The corporate social responsibility (CSR) disclosure was made mandatory in Malaysia in 2007 with the introduction of the CSR Framework by Bursa Malaysia. Since then, the practice of CSR disclosure is growing, as Malaysia joins global efforts towards sustainable development. Despite increased research on CSR; limited studies are assessing the relationship of specific dimensions – environmental, community, workplace and marketplace, towards dividend payout, which is crucial to investment and corporate financial decision making.\n\nMethod: The study involved 32 Malaysian public listed finance companies as of 2017. It deployed data from annual reports and databases. Additionally, the study used content analysis to measure the CSR disclosure score, and dividend payout was calculated from the database.\n\nResults: There was a significant correlation between community and workplace dimensions with dividend payout. Despite the absence of significant results, the regression analysis showed a positive relationship between community and workplace dimensions with dividend payout. Besides, there was an inverse relationship between the environmental and marketplace dimension with dividend payout. The results indicated that active involvement in the community dimension resulted from an immediate positive impact towards brand equity, attracting current and new customers, and therefore improving the earning levels and dividend payout. Additionally, greater participation in the workplace dimension solidifies employees' engagement and motivation, improves the productivity level, which can be translated into enhanced earning levels and dividend payout. Meanwhile, participation in environmental and marketplace dimensions requires a longer period to yield an impact, higher development expenditure, and involve sensitive information that might benefit competitors. Hence, companies tend to utilise internal funding instead of redistributing the wealth through dividend payout.\n\nConclusion: The study contributes to the literature of CSR by explaining the relationship of specific dimensions of environmental, community, workplace, and marketplace towards dividend payout using the evidence from the emerging economy.",
"keywords": [
"Environmental",
"Community",
"Workplace",
"Marketplace",
"Corporate Social Responsibility",
"Dividend Payout",
"Finance Companies",
"Malaysia."
],
"content": "Introduction\n\nCorporate Social Responsibility (CSR) has been around for decades, which was initially carried out voluntarily. Later, encouraged and enforced by governments and authorities, CSR is deployed to create a better sustainable business environment (Bursa Malaysia, 2012). However, there are mixed arguments in CSR, where some companies view it as capital reduction while others view it as value creation (Nekhili, Nagati, Chtioui & Rebolledo, 2017; Robinson, Kleffner & Bertels, 2011; Margolis & Walsh, 2003). Although the worldwide business environment started to boost CSR disclosure (PwC, 2017; KPMG, 2015), there is still room for further development of CSR practices, particularly for an emerging and developing market like Malaysia. At the start of 2017, CSR practice and disclosure in Malaysia started to surge since it was made mandatory by the government for publicly listed companies to disclose CSR initiatives in their annual reports (Bursa Malaysia, 2012). The CSR disclosure framework issued by Bursa Malaysia in 2006 governs the CSR disclosure in Malaysia. The framework consists of four dimensions of CSR, namely (1) environmental, (2) workplace, (3) community, and (4) marketplace (Bursa Malaysia, 2012). This framework governed public companies' CSR disclosure and was incorporated as a new rule in Bursa Malaysia Listing Requirement. Before 2006, CSR disclosure by Malaysian public listed companies was voluntary, and public listed companies' level of disclosure was not encouraged (Lim, Talha, Junaini & Sallehhuddin, 2008). Moreover, despite the enforced CSR disclosure, the framework does not contain details of measurement criteria of CSR disclosure; therefore, multiple formulas to measure the CSR disclosure level was proposed by a prior study (Mohanadas, Sallehhuddin & Lim, 2019; Lim et al., 2008; Williams & Ho, 1999; Hackston & Milne, 1996).\n\nTo date, numerous studies have analysed the CSR in Malaysia such as Sulaiman, Abdullah and Fatima (2014), Saleh, Zulkifli and Muhamad (2010), and Nik Ahmad, Sulaiman and Siswantoro (2003). Studies by Yam (2013) and Nik Ahmad and Haraf (2011) focused on CSR disclosure for a specific economic sector, i.e., property development. In general, studies found a significant increase in the extent and quality of CSR disclosure in Malaysia (Haji, 2013). There were also studies on the impact of CSR on organisational performance, such as financial performance by Selvarajah, Murthy and Massilamani (2018), tax aggressiveness by Mohanadas et al. (2019), and the antecedents of CSR disclosure by Lim et al. (2008). However, there are limited studies on the impact of CSR reporting on dividend payout even though it is one of the most crucial parts of corporate finance as investors use it to analyse the future cash flow of the business (Fama & French, 2001).\n\nAdditionally, dividend payout influences ethical investors decision in placing their money in socially, environmentally, and ethically compliant companies (Hellsten & Mallin, 2006). Besides, Cheung, Hu and Schwiebert (2018) and Benlemlih (2019) suggested that higher CSR performing companies in the United States, tend to pay higher dividends than lower-performing peers. Therefore, as Malaysia moves towards achieving the United Nation's Sustainable Development Goals (SDG), it is essential to determine the interactions of CSR reporting and dividend payout. Besides, investors may factor in CSR performance in determining dividend payout to make a better justifiable investment decision.\n\nMoreover, it helps to discover the extent of CSR influence on the distribution of wealth among companies. Hence, this study will examine the relationship of each dimension of CSR stipulated by the CSR Framework 2006 of Bursa Malaysia and dividend payout of public listed financial companies. This study attempts to answer the relationship between environmental dimension, community dimension, workplace dimension and marketplace dimension towards dividend payout. In short, the study intends to pioneer the investigation of specific CSR dimension performance on dividend payout in the Malaysian context, in particular among financial institutions.\n\nThe outcomes of this study contributed to the body of literature in several ways. First, this study provided new evidence on the relationship between CSR performance and dividend payout among companies, particularly finance companies in the emerging market. Previously, Hendijani Zadeh (2020), Sheikh (2020), Benlemlih (2019), Cheung et al. (2018), Samet and Jarboui (2017), and Rakotomavo (2012) examined this relationship; however, this study focused on the developed market which has a different economic policy, developmental rate, cultural and priorities. Moreover, Cheung et al. (2018) and Rakotomavo (2012) concentrated the analysis on overall CSR disclosure instead of specific CSR dimension. Besides, Hendijani Zadeh (2020), Sheikh (2020), and Samet and Jarboui (2017) excluded the financial sector in the final analysis. Second, despite the effort by Saeed and Zamir (2021) and Trihermanto and Nainggolan (2019) to assess the impact of CSR involvement on dividend payment in an emerging market, the findings remain inconsistent and inconclusive. Additionally, Nguyen and Nguyen (2021) attempted to evaluate the impact of CSR involvement among commercial banks in Vietnam; however, the study concentrated on measuring the risk-taking behaviour rather than a dividend payment. Therefore, this study offered new findings on the impact of specific CSR dimensions on dividend payout, particularly among financial institutions in the emerging market. Third, this study added to the literature of dividend payout antecedent by explaining the impact of non-financial factors, like CSR disclosure. The encouragement to examine non-financial factors towards dividend policy is emphasised by Pinto, Rastogi, Kadam and Sharma (2020) and Al-Najjar and Kilincarslan (2019). Besides, existing studies in emerging and developing markets like Budagaga (2020) and Dewasiri, Koralalage, Azeez, Jayarathne, Kuruppuarachichi and Weerasinghe (2019) heavily concentrated on financial factors towards dividend policy.\n\n\nLiterature review\n\nBroadly, there are two possible explanations for the relationship between CSR and dividend payout. First, companies enhance their involvement and participation in CSR to strengthen their brand reputation and secure public accolades (Cespa & Cestone, 2007). Second, CSR is one of the strategies to formulate a positive attitude among the public towards a particular company (Harjoto & Jo, 2014). The boost of the positive corporate image is expected to improve sales and protect companies from market uncertainties (El Ghoul, Guedhami, Kwok & Mishra, 2011), including competitors (Bae, El Ghoul, Guedhami, Kwok & Zheng, 2019). As a result, better sales and market share control shall contribute to the enhancement of revenue. Subsequently, as the earnings level improves, a company can announce a higher dividend payout to shareholders. Besides, CSR becomes a marketing and publicity tool for a company to maintain loyalty among existing customers as it creates a feeling of association with a positive brand. Then, the existing groups of current customers are expected to improve purchasing level, leading to better earnings and, eventually, a higher dividend payout. Additionally, CSR becomes a marketing tool to attract new customers by utilising strong brand associates with good deeds or philanthropic initiatives to a deprived community. Heal (2005), in summary, contended that an improved CSR involvement leads to better earnings through brand equity, a better connection with stakeholders, boost employee productivity, and improved asset allocation.\n\nSecondly, CSR relates to dividend payout by lowering the cost of capital. The greater involvement of companies in CSR activities usually leads to a better disclosure level of information on companies' profiles. As more details become public, it increases transparency and reduces information asymmetry (Chauhan & Kumar, 2018). This translates to a lower cost of gathering or collecting information about a particular company among investors, creditors, or financiers. Subsequently, it reduces the cost of issuing and raising capital among companies that actively participate in CSR programmes. Effective cost management leads to improvement of earnings level, which later translated to a higher dividend payout. From a different perspective, as argued by Benlemlih (2019) and Goss & Roberts (2011), less socially responsible companies (e.g., alcohol, tobacco and military & weaponry) commonly confront a higher cost of capital or exorbitant external financing. Consequently, these companies prefer to keep their cash for future internal funding than redistribute the wealth through a higher dividend payout.\n\nA study by Benlemlih (2019) observed 3040 companies in the United States from 1991 to 2012. The findings indicated that a strong performing of CSR companies tends to declare a higher dividend payout, while less performing CSR companies typically report a lower dividend payout. A further assessment evidenced that a strong performing of CSR companies' community, environmental, and workplace dimensions positively correlated with dividend payout. Only marketplace dimension had an inverse relationship with dividend payout. Benlemlih (2019) and Bah & Dumontier (2001) argued that the marketplace dimension instituted product development which involved strategic and sensitive information. Companies prefer to cover product innovation or product development expenditure through internal financing to avoid exposure to competitors. Hence, companies keep the cash within the organisation instead of redistributing the wealth through dividend payout. Earlier, Cheung et al. (2018) examined 1965 companies in the United States covering 1991 to 2010. The panel data set analysis also evidenced that a company with strong participation in CSR is positively related to a higher dividend payout.\n\nMeanwhile, a study by Kim and Jeon (2015) examined the relationship between CSR and dividend payout in Korea. The study found that the parent companies direct the dividend policy of multinational companies' subsidiaries in Korea. The findings also found a weak correlation between CSR and dividend payout among foreign subsidiaries compared to the local Korean companies. Additionally, Samet and Jarboui (2017) evaluated CSR involvement with dividend policy among European firms. The study observed 397 data of a firm from 2009 to 2014, which indicated that a socially responsible firm pays a higher dividend than a less socially responsible counterpart. Besides, using 17670 of the United States firm-year observations from 1991 to 2007, Rakotomavo (2012) established that a more mature company is willing to increase spending on CSR without lowering the expected dividend payout. Thus, there was a direct relationship between CSR spending and dividend payout. However, like Samet & Jarboui (2017), Rakotomavo (2012) also omits the individual CSR dimension analysis on dividend payout. In a more recent investigation, Hendijani Zadeh (2020) deployed 2,822 of the United States' firm-year observations of Standard and Poor's (S&P) 500 index firms from 2012 to 2019. The study examined the impact of environmental CSR and social CSR disclosures on companies' dividend payout. The findings indicated that the higher disclosure of both dimensions leads to a higher dividend payout. Additionally, the findings revealed that the dividend payout was more stable among firms with high environment CSR and social CSR disclosures than fewer disclosure firms. Meanwhile, Sheikh (2020) used the United States' 24,215 firm-year observations of the Morgan Stanley Capital International (MSCI) (previously KLD) database for 2003 to 2018. The findings discovered a positive relationship between CSR performance and dividend payment. Furthermore, the relationship was significant when companies operated in a less competitive market. However, there was a non-significant relationship between CSR performance and dividend payment among firms operating in a competitive market.\n\nIn an emerging market context, Saeed and Zamir (2021) checked the relationship of CSR involvement with dividend payout in India, China, Indonesia, Pakistan, Malaysia, Korea, Turkey, and Russia. The investigation selected the top 250 companies in terms of market capitalisation from each country. After several filtering considerations, the final sample covered 721 companies but omitting finance companies (India – 180, China – 162, Indonesia – 42, Pakistan – 50, Malaysia – 80, Korea – 109, Turkey – 51 and Russia – 47), covering the period of 2010-2018. The study also revealed a similar pattern, where there was an inverse relationship between CSR involvement and dividend payout in the understudy emerging markets. In terms of individual CSR effect, the study also found that community and environmental dimensions had an inverse relationship with dividend payout, with the community dimension experiencing greater magnitude than the environmental dimension. Besides, Trihermanto and Nainggolan (2019) observed 527 Indonesian firms' data (2008 – 2015) to assess the impact of CSR involvement towards dividend payment. The study found that there was a positive relationship between CSR expenses and firms' dividend payments. Similar positive relationships were also established for CSR social dimension and CSR environmental dimension. However, there was a negative relationship between CSR economic dimension and firms' dividend payment. The study measured CSR economic dimensions by considering the expenses spent for business partnership projects, community development and infrastructure projects. In addition, Nguyen and Nguyen (2021) evaluated 30 Vietnamese commercial banks' data for 2008 to 2017. Even though dividend payment was not directly measured, the variable was considered a form of risk, and the inability to meet the commitment was perceived to increase the banks' risks. Besides, the study did not count for specific CSR dimensions. However, the study found that financially constrained commercial banks reduced CSR expenses to manage risk like meeting dividend commitment, while financial unconstrained commercial banks were more likely to increase CSR expenses and exhibited a high risk-taking attitude.\n\nBased on the mentioned arguments, there are four hypotheses formulated in the current study to examine the relationship between each dimension of CSR disclosure and dividend payout. The hypotheses are as follow:\n\nThere is a positive relationship between the environmental dimension of CSR and dividend payout.\n\nThere is a positive relationship between the community dimension of CSR and dividend payout.\n\nThere is a positive relationship between the marketplace dimension of CSR and dividend payout.\n\nThere is a positive relationship between the workplace dimension of CSR and dividend payout.\n\n\nMethods\n\nThe four dimensions of CSR disclosure served as independent variables, and the dividend payout served as a dependent variable. Environmental dimension (CSR_E) focused on finance company's disclosure relating to environmental efforts. Community dimension (CSR_C) referred to the finance company's disclosure on contributing back to the community where the business is operating. The marketplace dimension (CSR_M) focused on the finance company's disclosure of products and services offered to the market and the concerned customers' satisfaction. The workplace dimension (CSR_W) refers to financing a company's effort to provide a suitable working environment that promotes equality, fairness, and safety. Finally, dividend payout (DivPay) concentrated on the percentage of dividend payment over the financial companies' earnings.\n\nAs of 2017, there were 32 public listed finance companies at Bursa Malaysia. According to Krejcie and Morgan (1970), a sample size of 28 is appropriate for a population size of 32. Nevertheless, the study captured and analysed the entire 32 finance companies. These finance companies were differentiated into five categories: credit service provider, insurance, banks, and exchange and investment holdings. In specific, the sample included 10 retail banks, one exchange, ten investment holding companies, eight insurance companies and three credit service providers (See Extended data A) (Sallehhuddin, Keong & Yatim, 2021a). 2017 Data was chosen for this study as it represented the complete fiscal year of finance companies' performance during the last year of the implementation of the National Transformation Policy by the sixth Prime Minister Najib Razak. The policy was ceased after the defeat of the ruling party since the independence in 1957-Barisan National (Alliance Front) in the 14th General Election in May 2018 (Nadzri, 2018)\n\nAnnual reports of finance companies in 2017 were referred to obtain data from each CSR dimension. In addition, the study also referred to Bursa Malaysia and Bloomberg databases for information on finance companies' dividend payout. Content analysis was used to analyse CSR disclosure performance from annual reports and databases. Content analysis has been widely deployed to measure CSR disclosure and it is considered to be the most reliable method (Parsa, Roper, Muller-Camen & Szigetvari, 2018; Zamir & Saeed, 2020; Haniffa & Hudaib, 2007). The variables were analysed by utilising the 120 measurement criteria adopted by Shirley, Suan, Leng, Okoth and Fei (2009), Williams and Ho (1999) and Hackston and Milne (1996). There were 47 environmental items, nine community items, 15 marketplace items, and 49 workplace items. The example of each CSR dimension's items is presented in Extended Data B (Sallehhuddin, Keong & Yatim, 2021b). The score of “1” was assigned for disclosure of CSR items while “0” for non-disclosure of CSR items. Then, the total score of each CSR dimension was computed in terms of percentage. Moreover, dividend payout is computed in a ratio by determining the amount the company pays its shareholder in the form of dividends from its earnings.\n\nData analysis consisted of univariate analysis, where descriptive statistic such as mean, standard deviation, minimum and maximum was presented. Then, bivariate analysis was deployed to analyse the relationship between each dimension with dividend payout. Subsequently, the multivariate analysis assessed the simultaneous interactions among multiple variables under study. Finally, the results of the multivariate analysis were also referred to for hypothesis testing. Analysis was carried out using SPSS 24.\n\n\nResults\n\nTable 1 depicts the descriptive analysis. These results show that there were finance companies without involvement in environmental and community-related CSR programmes. On average, finance companies recorded a higher involvement in community-related programmes with 65%, followed by involvement in marketplace-related projects. Conversely, the lowest involvement of finance companies was in environmental-related programmes. In addition, on average, the dividend payout for finance companies was 41.18.\n\nTable 2 shows the correlation analysis. There was a significantly positive correlation between the community dimension and workplace dimension with dividend payout. In addition, there was a positive and non-significant correlation between environmental dimension and marketplace dimension with dividend payout. Besides, there was a strong and significant correlation among the four dimensions of CSR. For instance, the workplace dimension was strongly and significantly related to environmental, community, and marketplace dimensions. It implied that finance companies could actively engage the workforce or garner employees support to execute CSR programmes. It also reflected that finance companies organised awareness workshops or provided training for employees to familiarise the workforce in CSR initiatives. The strong correlation could also be attributed to a series of CSR initiatives executed by employees that benefited from more than one dimension concurrently.\n\n** Correlation is significant at the 0.01 level (2 – tailed).\n\n* Correlation is significant at the 0.05 level (2 – tailed).\n\nTable 3 indicates the multiple regression analysis results. The results yielded the R-square value of 0.206, indicating 20.6% of the variation in dividend payout was explained by the four dimensions of CSR. Besides, the regression equation can be represented as follows:\n\nThe equation can be interpreted as follows:\n\na. For every unit increase in environmental, dividend payout decreases by 9.606 units, provided other independent variables remain unchanged.\n\nb. For every unit increase in a community, dividend payout increases by 32.316 units, provided other independent variables remain unchanged.\n\nc. For every unit increase in the marketplace, dividend payout decreases by 27.895 units, provided other independent variables remain unchanged.\n\nd. For every unit increase in the workplace, dividend payout increases by 52.487 units, provided other independent variables remain unchanged.\n\nWorkplace dimension had the highest impact on dividend payout, followed by community dimension. In terms of significant effect, the environment, the community, and the workplace had p-values of 0.798, 0.336, and 0.407, respectively. Hence, all four dimensions of CSR had a p-value of more than 0.05, indicating no significant impact on dividend payout. Despite non-significance indication for all four dimensions, the regression found positive relationships for community and workplace CSR dimension with dividend payout; hence, the study found support for hypotheses 2 and 4; however, the regression found negative relationships for environmental and marketplace CSR dimension with dividend payout; hence, the study did not find support for hypothesis 1 and 3.\n\n\nDiscussion\n\nThese findings were consistent with studies by Senawi, Abdul Rahman, Ahmad and Che Pin (2016) and Shirley et al. (2009), where like other sectors, finance companies also placed a higher weight on the community dimension, as compared to other dimensions of CSR. The community dimension is believed to be the easiest and quickest route to achieve immediate results of projecting the companies' positive brand, reputation, image, goodwill and developing a positive attitude in public (Harjoto & Jo, 2014). The community dimension is about giving back to the public or community in the form of cash, non-cash or a kind gesture to society. The benefits are instantly reaped from activities of donating cash to a non-profit organisation and setting up scholarship schemes for underprivileged society. Companies can expect immediate recognition by contributing to community dimension activities, whereas investing in other dimensions like environmental, marketplace and workplace may not produce the immediate results or impact (Brown, Helland & Smith, 2006). For instance, for the environmental dimension, the public may not be interested or keen on the efforts of companies in building a green office or minimising carbon release. Investing in the workplace dimension may just benefit the employees, as compared to the general public at large. Therefore, it is expected that the community dimension remains the primary and the easier route to opt for companies to contribute in terms of CSR. A company that contributes back to society via community dimension usually derives an instant good corporate image. Furthermore, it is the public who become a major beneficiary as companies increase involvement or contribution through the community dimension. Earning a good corporate image at the same time will grant invisible advertising and marketing towards the company. The public has a higher tendency to accept a company with a good corporate image, as compared to a not known company, especially in the financial sector. Additionally, a conscious investor will only invest into or engage financial institutions that he or she believes in or is trustworthy. Moreover, investors easily obtain visible information about companies' active involvement in CSR; hence, it reduces the asymmetrical information concern, reduces the cost of capital, and lower the companies' financial risk (Harjoto & Jo, 2014). Additionally, Brown et al. (2006) also argued that involvement in the community dimension of CSR could help to boost companies' positive standings among regulators or authorities, in particular during a situation of possible litigation orders.\n\nBased on the findings, another considerable point is companies' involvement in the workplace dimension of CSR. A more active employee engagement via the workplace dimension is expected to benefit companies. An active employee engagement signals concern and commitment of companies towards personnel well-being. It is expected to improve the productivity level, which will be translated into an improved earnings level or reduced operating cost per employee. A level of satisfaction among employees is expected to improve as more resources are channelled to strengthen the occupational safety and health aspect in companies. By doing so, it enhances the conducive and sound working environment. In fact, studies by Verwijmeren and Derwall (2010), Berk, Stanton and Zechner (2010), and Bauer, Derwall and Hann (2009) evidenced that companies with extensive employee engagement programmes enjoy better credit ratings and reduce related multiple risks, including litigation risks by unions or workers' associations or bankruptcy filings. In short, Benlemlih (2019) argued that enhancing workplace dimension engagement shall lead to better employees' treatment, solidify staff morale, and support, and enable companies to focus more resources in managing strategic initiatives, including wealth distribution matters to shareholders.\n\nIn terms of managerial and practical implications, financial institutions will continue aggressively to participate and support community-related programmes in CSR initiatives. Such initiatives send signals to stakeholders, especially the society or non-profitable organisations, that finance companies have a strong corporate citizenship behaviour by providing scholarships to needy children, extending financial aid to vulnerable groups, or sponsoring public amenities projects. The strong involvement of finance companies in community-related programmes contributes towards strengthening the branding and improving the earnings level. Therefore, it enhances the dividend payment to shareholders. Furthermore, finance companies shall continue to aggressively enhance workplace-related programmes in the CSR initiatives. Finance companies may improve the resources allocation to enhance the employees' health and safety conditions physically, emotionally, mentally, ethically, spiritually, and psychologically. Finance companies also will continue to offer better remuneration, benefits, and engagement with their employees. The strong involvement in workplace-related programmes can boost the morale and motivation of employees, which translated to higher productivity and improved earnings level. Consequently, it improves the dividend payment to shareholders. In addition, better treatment of employees improves the reputation of finance companies among regulators and oversight agencies, which can help to reduce the cost of capital when an additional cash injection is needed or required. It helps to monitor and reduce the cost of issuing debt or capital, which later translated into better earnings and a boost in the dividend payout. On the other hand, the findings inform regulators and policymakers that necessary improvements such as tax incentives or other rewards schemes will be designed to encourage greater participation of finance companies in the environmental and marketplace dimension of CSR. For instance, finance companies will be encouraged to offer innovative products to support more economic activities that contribute positively to sustainable development and environmentally friendly product development. Without additional incentives, finance companies are reluctant to support green economy sectors, which have a longer period of achieving economies of scale or breakeven points. Besides, investors may consider adopting companies with strong involvement in the community dimension and workplace dimension of corporate social responsibility, as compared to companies with participation in marketplace dimension and environmental dimensions. These findings indicated that companies that placed a greater contribution to community and workplace CSR tend to pay a higher dividend.\n\nMoreover, in terms of theoretical implication, the findings contributed to the body of knowledge by zooming out the impact of specific CSR dimensions on dividend payout. Previously, Saeed and Zamir (2021) found that environmental and social dimensions have a negative relationship towards dividend payout in a selected emerging market, including Malaysia. Therefore, the findings of this study corroborate with Saeed and Zamir (2021) in the context of the environmental CSR dimension; however, not consistent in the context of social or community CSR dimensions. The mixed findings reflect the agency problem in both financial and non-financial companies. Managers tend to opportunistically use CSR disclosure to project favourable news or report unfavourable news through a positive tone. Besides, managers may take advantage of the CSR aspect by allocating more resources in a particular dimension while providing fewer resources in other particular dimensions in order to satisfy the shareholders or to gain shareholders' trust toward their managerial stewardship. Furthermore, the findings of this study corroborate with Trihermanto and Nainggolan (2019) in the context of the direct relationship of community or social CSR dimension with dividend payout. In fact, both studies found evidence that firms in the Indonesian and Malaysian markets prefer to participate more in the social dimension of CSR (etc., education sponsorship, charitable donation, social contribution) compared to other dimensions. In addition, the investment in the social CSR dimension improves as the firms reach a more mature stage of the corporate life cycle. However, the findings of the current study, which discovered a negative relationship between environmental CSR dimension and dividend payout, contradict Trihermanto and Nainggolan (2019), which found a direct relationship. Additionally, the findings of this study are consistent with Nguyen and Nguyen (2021), as both studies found a negative relationship between environmental and marketplace CSR dimensions with dividend payout. Nguyen and Nguyen (2021) argued that banks in an emerging market such as Vietnam prefers to spend less on CSR aspects, as they are more concerned about meeting possible future risks or shocks, like sudden dividend requests or pressure of higher dividend payment from shareholders. The consideration is prevailing if the banks are in financial constraint or difficult situation. Banks are found to spend more on CSR especially social and workplace dimensions, if they are financially unconstraint, have large resources to meet the future obligation and risk, including dividend payment from shareholders, or the investment in those CSR components provide greater returns and benefits, including reducing reputational, systematic, total, and idiosyncratic risks. Besides, the findings of the current study are consistent with Samet and Jarboui (2017). Both studies found a direct relationship between the social CSR dimension with dividend payout. In the same vein, allocating more resources for the social or community CSR dimension explains the commitment of financial and non-financial companies towards fulfilling and balancing the needs or expectations of various stakeholders, without compromising the obligation to meet shareholders' expectation of better returns in terms of dividend payout. Finally, the findings of the current study added to the body of literature, especially in improving the understanding of non-financial factors effects on corporate dividend policy. Consistent with the earlier work of Rakotomavo (2012), Samet and Jarboui (2017), Benlemlih (2019), and Trihermanto and Nainggolan (2019), the findings revealed the influence of non-financial factors, i.e., environmental, social, marketplace and workplace CSR dimensions towards dividend payout even among financial institutions in an emerging market. The findings also uphold the revelation by Girerd-Potin, Jimenez-Garces, and Louvet (2014) that investors and shareholders do matter to a specific CSR dimension and its eventual impact on corporate dividend policy.\n\n\nConclusions\n\nThe findings achieved the underlying objectives of the study. The results showed that there is a significantly positive correlation between community dimension and workplace dimension with dividend payout. However, there is a positive and non-significant correlation between environmental and marketplace dimensions with dividend payout. The regression analysis further indicated that there are positive relationships between community dimension and workplace dimension with dividend payout even though the relationships are non-significant. Additionally, there are negative relationships between the environmental dimension and marketplace dimension with dividend payout, and the relationships are also non-significant.\n\nThe study is limited by only focusing on the impact of CSR dimensions on dividend payout among public listed finance companies in Malaysia. Hence, the finding shall be generalised incautious for other sectors, as well as for other jurisdictions. In addition, the data concentrated on one financial year only, which might be influenced by specific events during the year of understudy. For future studies, a longitudinal approach could be adopted to assess the impact of CSR on dividend payout periodically. In addition, future studies may also extend the analysis of CSR disclosure impact on dividend payout among non-financial companies. Besides, future studies shall encompass other emerging markets' financial institutions such as ASEAN for comprehensive comparative analysis, as financial institutions play significant roles in socioeconomic well-being among developing nations.\n\n\nData availability\n\nFigshare: The effect of corporate social responsibility on Malaysian financial institutions' dividend payout, https://figshare.com/s/72c59755548ecf0b5d9e (Sallehhuddin, Keong & Yatim, 2021a).\n\nThis project contains the following underlying data:\n\nData file. Consist of data for descriptive analysis, correlation analysis and multiple regression analysis\n\nFigshare: The effect of corporate social responsibility on Malaysian financial institutions' dividend payout, https://figshare.com/s/688662717c1d8022d1b6 (Sallehhuddin, Keong & Yatim, 2021b).\n\nThis project contains the following underlying data:\n\nData file A. List of Finance Companies\n\nData file B. Example of CSR Measurement Criteria (extract of items from Shirley et al. (2009), Williams and Ho (1999) and Hackston and Milne (1996).\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\nAuthor contributions\n\nConceptualisation, AS, TBK and NMY; methodology, AS, TBK and NMY; formal analysis, TBK; investigation, AS and TBK; writing—original draft preparation, AS, TBK, and NMY; writing—review and editing, AS, and NMY; supervision, AS.",
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}
|
[
{
"id": "119881",
"date": "20 Jan 2022",
"name": "Shaista Wasiuzzaman",
"expertise": [
"Reviewer Expertise Corporate governance",
"financial management",
"investments."
],
"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 an interesting one. However, there are a few improvements that can be made to the study:\nThe motivation needs to be improved and made more concise. There is a lot of discussion in the introduction regarding CSR, but the motivation to relate it to dividend policy is not strong. A discussion on why dividend policy is important, why it is an important issue in Malaysia and how it can be influenced by CSR would strengthen the motivation of the study. So, less focus on history and background and more on the motivation of the study.\n\nAlso, it would be good if you can focus the issue to finance companies instead of in general. Only in the fifth paragraph, finance companies are mentioned. Why is CSR and dividend payout important to be studied in finance companies/institutions? What is special about financial institutions in Malaysia re: CSR and dividend payout?\n\nPlease provide a summary of the results of the study in the introduction.\n\nPlease be careful... is it CSR dimensions or CSR performance/involvement (in paragraph before H1 and in methods section)? This is because the discussions in the literature review is all on CSR involvement/performance and not on disclosure.\n\nSince the title and the objective of the study is to investigate the relationship of CSR with dividend payout, I would expect a hypothesis on the overall CSR measure with dividend payout.\n\nI would expect a discussion on why you have chosen finance companies as the focus of your study.\n\nI would also recommend including the overall CSR dimension instead of only its dimensions.\n\nThe reason for using year 2017 as being the implementation of the National Transformation Policy does not seem convincing. What does the policy have to do with CSR?\n\nFor results in Figure 1, it would help if you can provide some reasons why there is higher involvement in community-related programmes and lower in environmental-related ones.\n\nI would suggest to include some control variables in your model.\n\nThe correlations between the dimensions of CSR are quite high, especially between CR_C and CR_W. This indicates the issue of multicollinearity. This is also shown with high VIF of CR_W being greater than 4. This is a problem when it comes to regression analysis.\n\nIs the significant change value greater than 0.05? If it is, then it indicates a problem with your model and your regression results are invalid.\n\nThe problems with multicollinearity and no control variables could be the reason why your regression results are found to be insignificant. Also, since your data is across companies, you should check for heteroscedasticity.\n\nUnfortunately, because all your independent variables are insignificant, the discussion provided and the managerial implications do not hold. As these variables do not affect dividend payout significantly, why would managers be worried about it?\n\nOverall, I feel that the analysis and the model need to be improved.\n\nThere are errors in language that need to be corrected.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "119878",
"date": "10 Feb 2022",
"name": "Bakhtiar Alrazi",
"expertise": [
"Reviewer Expertise Sustainability reporting",
"corporate governance",
"stakeholder engagement"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, the manuscript brings an interesting issue that has not been well explored in the extant literature. However, there are few areas that could be addressed by the authors to further improve the manuscript.\nTitle\nSince the findings from the regression analysis do not show any significant effect of corporate social responsibility on the dividend payout (although correlation analysis demonstrates such a relationship), it is less appropriate to use it in the title as if the cause-and-effect relationship is evident from the findings.\nIntroduction\nThere should be a more enhanced discussion on the importance of investigating the influence of CSR on dividend payout and the decision to focus on financial institutions, other than being lacking in the literature.\n\nThe first sentence in the fourth paragraph is more appropriate to be the last sentence of the third paragraph as it deals with the reason for examining the impact of CSR on the dividend payout.\n\nInclude a paragraph at the end of the section to describe the structure of the manuscript.\nLiterature Review\nThis section needs to be re-arranged to improve the flow of discussion. Currently, it has three broad elements – the arguments, prior literature and hypotheses.\n\nThe authors may want to begin the section with a discussion of prior literature. Since the central focus of the research is on the dimensions of CSR, it is worthy to describe each of the dimensions in this section. Currently, these dimensions are described briefly in the Methods section. For the discussion of prior empirical findings, it shall follow a certain theme (e.g., by country, by scope of CSR – overall, dimensions, etc.). The discussion shall bring the readers to the identification of research gaps that the authors intended to address.\n\nThen, the section shall provide the arguments which link CSR and dividend payout. Is there any specific theory (or theories) that can be used to predict or explain the relationship? Previous literature have used one, or a combination, of the following theories: signaling theory; stakeholder theory; voluntary disclosure theory; life-cycle theory; and agency theory (e.g., Hendijani Zadeh, 20211; Sheikh, 20222; Saeed & Zameer, 20213; Benlemlih, 20194; Cheung et al., 20185; Samet & Jarboui, 20176; Rakotomavo, 20127). Interestingly, the authors mimicked the arguments used by Cheung et al. (2018)5; however, Cheung et al. (2018)5 was not cited in the arguments’ paragraphs (i.e. the first two paragraphs in the Literature Review section). Also, while Cheung et al. (2018)5 predicted a negative association between CSR and dividend payout (based on cost of capital argument), the authors predicted the opposite (based on a ‘positive relationship’ stated in the hypotheses). As such, the discussion on such a relationship needs to be strengthened. The discussion can begin with general premise of the theory before going into more specific elaboration into the relationship being investigated. By doing this, it can improve the development of hypotheses which currently looks like a mere listing of hypotheses.\n\nIt is not clear as to why the hypotheses only focused on CSR dimensions but neglected the overall CSR.\nMethods\nThe research is cross sectional in nature in which the authors chose year 2017 as the year of analysis. First, the choice of 2017 is not well supported. The CSR Framework was introduced in year 2006 (made effective in year 2007) and has been superseded by a new requirement for sustainability statement. Second, based on the Literature Review section, most of the existing research conducted in the area used several years of data. Although it is stated in the limitations of the research, the fact that the authors did not find any significant association from the regression analysis, it could be due to problem with the data. Consistent with prior literature, it is more appropriate if the data were collected for several years (e.g., 2007 – 2017).\n\nThe research only analysed annual reports for CSR. Over the years, there is an increasing evidence of companies using a stand-alone report (e.g., sustainability report) and company website to communicate their CSR information to stakeholders.\n\nThe guidelines used to measure CSR information were about eight years old (i.e. between 1996 and 2009). How did the authors ensure the items included are still valid/relevant? Did the authors make attempt to benchmark the items with guidelines published by other authoritative organisations such as GRI and Bursa Malaysia?\n\nThere are 120 measurement criteria used for CSR. However, the authors only provided a sample of 20 items in the Data file. To ensure full reproducibility of the research, it is suggested for the authors to include all 120 CSR disclosure items.\n\nOne of the main issues inherent in content analysis is subjectivity of the scores assigned to measure the disclosure level. How did the authors mitigate this issue?\nResults\nThe analysis is based on a small number of observations (n = 32). It is more often for this type of research utilising data of several years. The regression model only includes the main variables (CSR) without any control variable. As a result, none of the main variables are statistically significant and the model is more likely not significant. All these issues, taken together, question the rigour of the research.\n\nThe third paragraph in page 8 needs to be rephrased. Initially, the authors stated that “Workplace dimension had the highest impact on dividend payout”. Then, it is claimed that “…no significant impact on dividend payout. The authors next concluded, based on positive coefficients, that the findings support hypotheses 2 and 4. Is it appropriate to make such a conclusion when the coefficients are not statistically significant? This is contradicting with objectivity as one of the hallmarks of scientific research.\nDiscussion\nNone of the main variables are significant. Therefore, it is not convincing as to what extent the discussion presented really relate to the actual findings of the research.\nConclusions\nThe conclusion needs to better reflect the regression analysis i.e. CSR did not affect the dividend payout of the Malaysian financial institutions.\nReferences\nInconsistent referencing, e.g., in page 3, it is written as Nik Ahmad and Haraf (2011) but in the references list, it is Ahmad and Haraf (2011).\n\nSome of the references denoted ‘in press’ have been published. Update the references with the latest publication year, volume, number and page number (if any).\nLanguage and typographical errors Below are some language and typographical errors that could be identified. Authors are recommended to check throughout the manuscript for any other error.\nPg. 3: “At the start of 2007,”\n\nPg. 3: “…the relationship between each dimension of CSR…”\n\nPg. 3: “…the effect of environmental dimension, community dimension… towards dividend payout”\n\nPg. 4: the numbers’ formatting. Use 1,000 separator (,) more consistently, e.g., 3040 vs 2,822\n\nPg. 4: “…strong performing of CSR companies…” or “strong CSR performing companies”? Check also for the appropriateness of “less performing CSR companies”\n\nPg. 5: Check for the appropriateness of “…dividend payout in the understudy emerging markets”.\n\nPg. 5: Consistency in writing number i.e., “…10 retail banks, one exchange, 10 investment holding companies…”\n\nPg. 5: “2017 data was chosen…”\n\nPg. 6: “…the dividend payout for finance companies was 41.18%”\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": []
}
] | 1
|
https://f1000research.com/articles/11-47
|
https://f1000research.com/articles/10-1246/v1
|
06 Dec 21
|
{
"type": "Research Article",
"title": "Inflammatory laboratory findings associated with severe illness among hospitalized individuals with COVID-19 in Medan, Indonesia: a cross-sectional study",
"authors": [
"Darmadi Darmadi",
"Cennikon Pakpahan",
"Riska Habriel Ruslie",
"Andri Rezano",
"Darmadi Darmadi",
"Riska Habriel Ruslie",
"Andri Rezano"
],
"abstract": "Background: Coronavirus disease (COVID-19) is still a global health problem. COVID-19 patients with severe pneumonia have a higher risk for critical illness, mostly complicated by acute respiratory distress syndrome. The inflammatory response is critical, and the cytokine storm increases severity of COVID-19. Many factors could be associated with a cytokine storm but these are incompletely understood. The aim of this study is to present characteristics of patients with COVID-19 and explore the clinical and inflammatory parameters of severe and critically ill COVID-19 patients in the intensive care unit (ICU). Method: The cross-sectional study was conducted in all severe COVID-19 patients admitted to the ICU. Peripheral blood was taken for laboratory examination within 24 hours of admission. Hematologic parameters, serum electrolyte, renal function, liver function, pancreas enzyme, D-dimer, inflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (CRP) were assessed in this study. Comparison analyses were done between sex, comorbidity existed, body mass index (BMI), and vaccination status. Results: A total of 80 subjects were included in the study. The most frequent comorbidities found among the subjects were obesity (36.35%) and diabetes (22.5%). Only 13.75% of subjects were vaccinated. Laboratory results indicated leukocytosis and neutrophilia, with neutrophil-lymphocyte-ratio (NLR) of 7. The mean inflammatory findings (IL-6, IL-10, TNF-alpha, IFN-gamma, MCP-1), D-dimer, CRP, and lipase increased. Lipase levels were higher in men (p=0.003) and in comorbidity groups. No significant differences found with different BMI groups. Lipase, IL-6, and MCP-1 levels were significantly higher (p=0.019, <0.0001, and 0.03, respectively) in the non-vaccinated group. Conclusions: Most patients with severe COVID-19 have comorbidities and increased inflammatory markers.",
"keywords": [
"COVID-19",
"inflammatory",
"cytokine",
"comorbid",
"good health",
"well-being",
"vaccination"
],
"content": "Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the cause of the catastrophic coronavirus disease (COVID-19) pandemic that began in January 2020.1,2 It has claimed 4.4 million human lives as of 22 August 2021.3 By August 2021, 4,043,736 cases were reported in Indonesia with 130,182 deaths.4 COVID-19 has a fatality rate of 2.3%, less than both the severe acute respiratory syndrome coronavirus outbreak (SARS-CoV) (9.5%) in 2003 and the Middle East respiratory syndrome coronavirus outbreak (MERS-CoV) (34.4%) in 2012.5 The outbreak initially was linked to the Hua Nan seafood and wet animal market in Wuhan.6\n\nThe SARS-CoV-2 infection varies from asymptomatic, mild upper respiratory tract illness, and severe pneumonia with respiratory failure and death.7 Severe patients with COVID-19 usually present with respiratory rates greater than 30 breaths/minutes, oxygen saturation (SpO2) less than 93%, and greater than 50% lung infiltrates, and are at higher risk for clinical deterioration and critical illness.8 Acute respiratory distress syndrome (ARDS) was the most common complication occurring in 60-70% of patients admitted to the intensive care unit (ICU).9 ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide.10 This wide range of differences is presumably caused by the atypical disease process in ARDS, suggesting non-effectivity of mechanical ventilation in reducing lung injury.11 Mortality outcomes could be influenced by age, sex, race, chronic illness, comorbidities, insurance, geographic location, and medical management.12–15\n\nThe inflammatory response plays a critical role in COVID-19, and the inflammatory cytokine storm increases the severity of COVID-19.16,17 Periphery blood inflammatory factors such as interferon (IFN)-gamma, tumor necrosis factor (TNF), interleukin (IL)-10, IL-6, and monocyte chemoattractant protein-1 (MCP-1) may increase during COVID-19 infection.18–20 Many factors including sex, body mass index (BMI), comorbidity, and vaccination status could be associated with the incidence of the cytokine storm and severe COVID-19.18,21–23 The cytokine storm is crucial to the progression of COVID-19 and might lead to ARDS and death.24 Patients who survive from cytokine storms tend to suffer long-term lung damage and fibrosis, causing impairment in pulmonary function and lower quality of life.25\n\nIn Indonesia, resources for the management of COVID-19, particularly laboratory parameters are still constrained. This issue brought up the need for simple approaches to detect cytokine storms in patients with COVID-19, which could help stratify the risk of morbidity and mortality in COVID-19 patients at the time of hospitalization. In this study, we present details of patients with COVID-19 hospitalized in the ICU of Mitra Medica General Hospital in Medan, North Sumatera, Indonesia. We aim to explore the clinical and inflammatory parameters of severe and critically ill COVID-19 patients in the ICU.\n\n\nMethods\n\nThis study was approved by the ethics committee of Universitas Sumatera Utara (Ethical clearance number 453/KEP/USU/2020). The ethics committee is in charge for North Sumatera province including this study location. Informed consent was obtained before data collection. In this study, written informed consent was obtained from each patient’s proxy if the patient was unconscious. Otherwise, written informed consent was obtained from corresponding patient.\n\nThe cross-sectional study was conducted in all COVID-19 cases (confirmed by the RT-PCR test) admitted to the ICU of Mitra Medica General Hospital Medan, Indonesia, between May and June 2021. Inclusion criteria were all subjects classified as severe COVID-19 according to the World Health Organization guidelines.26 Diagnosis of severe COVID-19 was made if subjects met one or more of the following criteria: dyspnea, respiratory rate of 30/min, SpO2 of 93%, PaO2/FiO2 ratio less than 300 mmHg, greater than 50% lung infiltrate on CT scan within 24-48 hours, and those with respiratory failure, septic shock, and/or multiple organ dysfunction.26\n\nDemographic data, clinical history, and vaccination status of patients were collected from the patient’s medical record. BMI data were calculated from the patient’s weight and height. A total of 10 mL peripheral blood was taken for laboratory examination within 24 hours after the patient was admitted to the ICU. Laboratory parameters included in this study were hematologic parameters (hemoglobin, leukocyte, thrombocyte, neutrophil, lymphocyte, monocyte), serum electrolyte (sodium, potassium, chloride, calcium), renal function (urea, creatinine), liver function [aspartate transaminase (AST); alanine transaminase (ALT)], pancreas enzymes (amylase, lipase), D-dimer, inflammatory cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10, MCP-1), and C-reactive protein (CRP).\n\nThe inflammatory cytokines were analyzed with the following kits: IL-6, Human IL-6 Quantikine ELISA kit Immunoassay (R&D System, Minneapolis, MN, USA); IL-10, Human IL-10 Quantikine ELISA kit Immunoassay (R&D System, Minneapolis, MN, USA); MCP-1, Human CCL2/MCP-1 Quantikine ELISA kit Immunoassay (R&D System, Minneapolis, MN, USA); IFN-gamma, Human IFN-gamma Quantikine ELISA kit Immunoassay (R&D System, Minneapolis, MN, USA); TNF-alpha, Human TNF-alpha Quantikine ELISA kit Immunoassay (R&D System, Minneapolis, MN, USA).\n\nStatistical analysis was done using GraphPad Prism version 8.0. Normality test with Kolmogorov-Smirnov test was conducted to determine distribution normality of the data. Parametric data were presented in mean ± standard deviation, while non-parametric data were presented as median and interquartile range. Data were compared between genders, subjects with comorbidity and without comorbidity, BMI, and vaccination status. Patients’ BMI were classified as underweight, normal weight, overweight, and obese based on BMI criteria for Asia.27 The differences between two groups were tested with the independent t-test and the Mann-Whitney test. T-test was utilized for parametric data and Mann-Whitney test for non-parametric one. Meanwhile, differences between groups of more than two were done with the one-way ANOVA test for parametric data and otherwise with the Kruskal Wallis test. Statistical analysis was done within 95% confidence interval. Significance was established based on p-value of <0.05.\n\n\nResults\n\nA total of 80 subjects were included in the study. The demographics data is presented in Table 1. The mean age of all the subjects was 59 years old. There were more male subjects. The most frequent comorbidity found among the subjects was obesity (36.35%), followed by diabetes (22.5%). Only 11 subjects (13.75%) were vaccinated in this study.\n\nTable 2 presents the laboratory results from this study. Leucocyte and neutrophil percentage increased in the subjects. Neutrophil to lymphocyte ratio (NLR) was 7. The inflammatory findings were increased in severe COVID-19 patients in the study compared to normal value. D-dimer as a coagulopathy parameter increased above the normal range in this study. CRP, ALT levels, AST levels, and lipase also increased in the subjects. Other parameters including serum electrolyte levels and renal function were relatively within normal reference value. Results of comparison analysis between males and females are shown in Figure 1. Lipase levels were higher in men (129.5 (±52.32), p = 0.003). Analyses between BMI groups are presented in Table 3. There are no significant differences found between different BMI groups. As for analysis regarding non-comorbid and comorbid groups, lipase levels were higher in groups with comorbidity compared to those without comorbidity (shown in Figure 2). Between the vaccinated and non-vaccinated groups, results indicated a significantly higher level of lipase, IL-6, and MCP-1 (p-value = 0.019, <0.0001, and 0.03, respectively) in the non-vaccinated group (Figure 3).\n\nLipase levels were significantly higher in men (129.5 (±52.32), p = 0.003). C-reactive protein, Aspartate aminotransferase levels, and interferon-gamma were also higher in men. Women, though not significant, had higher levels of D-dimer, Alanine Aminotransferase levels, amylase, tumor necrosis factor-alpha, interleukin-6, interleukin-10, and monocyte chemoattractant protein-1.\n\nLipase levels were significantly higher in patients with comorbidity. Most laboratory parameters were higher in patients with comorbidities, except for aspartate aminotransferase levels and Interferon-gamma.\n\nLipase levels, interleukin-6 levels, and monocyte chemoattractant protein-1 levels were significantly lower in vaccinated patients (p-value = 0.019, <0.0001, and 0.03, respectively). Aspartate Aminotransferase levels and amylase levels also were lower in vaccinated subjects.\n\n\nDiscussion\n\nMore men were included in our study group with severe COVID-19, suggesting that they suffer from the severe form of COVID-19 compared with women. Most recent studies suggested that men also tend to present more severe forms of the disease and have a higher rate of mortality.28 The number of men is 2.4 times that of women in the deceased patients. While men and women had the same susceptibility, men were more prone to dying.28,29 Potential risk factors have been suggested as different behavior between genders, genetic and hormonal factors, and the influence of sex genetics in viral pathogenesis.29 Risky behaviors such as smoking and alcohol consumption have been reported in more men than women,30 and these behaviors increase risks for hypertension, cardiovascular disease, and chronic pulmonary disease, which could exacerbate severity and susceptibility to COVID-19. The mechanism of SARS-CoV-2 infection is regulated by the expression of ACE-2 and TMPRSS2 genes. These factors are often associated with sex, for instance the ACE-2 gene is found on the X-chromosome. Inactivation of this gene has been associated with the incidence of COVID-19 in males and females.31 The gene that transcribes TMPRSS2 is influenced by androgens that the presence of androgens promote the expression of TMPRSS2. TMPRSS2 act as co-receptor for SARS-CoV-2 cell invasion and it’s high expression will lead to increased susceptibility for COVID-19.32,33\n\nThe mean age of all the subjects in our study was 59 years old, with the youngest subject over 50 years old. Older people were more sensitive to SARS-CoV-2 infection and had a higher positive rate than younger age.34 Older subjects are also associated with increased mortality from COVID-19 due to poorer lung function and the likelihood of comorbidities when compared to younger patients.34,35 Aging significantly causes an increase in pro-inflammatory cytokine levels (CRP, D-dimer, Procalcitonin, and IL-10).36 Older patients normally experience a decline in physiological immune function and immunosuppression, thus making it difficult for them to control pro-inflammatory responses.35\n\nObesity is one comorbidity related to severe COVID-19.37 Subjects with a BMI of less than 18.5 kg/m2 and greater than 25 kg/m2 have a higher risk for fatal illness.38 In this study, a total of 36.35% were obese and 6.25% were underweight based on Asian BMI criteria. Obesity is one of the risk factors for cardiometabolic disease and is reported to cause immune system dysregulation. Obese patients have the highest risk for longer hospitalization and death due to COVID-19.39 Adipocytes could increase the inflammatory response by stimulating macrophages to produce interleukins (IL-1, IL-6, IL-8, IL-10) and TNF-alpha. Meanwhile, underweight COVID-19 patients are at risk of developing acute kidney injury, which could worsen the patient’s condition.40 In this study, laboratory parameters were not significantly different within various BMI groups. This might also be influenced by other conditions of the patients.\n\nDiabetes mellitus is also widely associated with the incidence of COVID-19.41 Increased glucose metabolism in patients with diabetes could directly enhance the replication of the SARS-CoV-2. Increased glucose escalates the production of mitochondrial reactive oxygen species and activates hypoxia-inducible factor 1α.42 Insulin resistance itself is associated with impaired response to IFN type 1, thus generating a high viral load and inhibiting body inflammatory response.43\n\nVaccination is part of the prevention program against SARS-CoV-2. The vaccine promotes antibody production to prevent COVID-19.44 Administration of the vaccine also effectively reduces the severity of the disease.23 In this study, 86.25% of patients were reported as non-vaccinated. Several parameters were significantly different between the vaccinated and non-vaccinated groups. Lipase, IL-6, and MCP-1 were higher in the non-vaccinated group. Increased lipase and IL-6 indicate an inflammatory response and imply more severe disease.7 On the other hand, MCP-1 is suspected to be related to inhibition of IFN-signalling.45 IFNα and IFN-β have antiviral activity; thus non-vaccinated individuals tend to have poorer immune response due to low antiviral activity.46\n\nSubjects in this study had an increased leukocyte count and lymphopenia. This finding was also found in the meta-analysis by Huang et al., which reported patients with severe COVID-19 tended to have higher leukocyte counts and lower lymphocyte counts compared to non-severe illness.47 Leucocytosis may be present due to co-infection with bacterial pneumonia, and steroid medication given to those with severe illness is known to induce leucocytosis or variability in the immune response.48 Lymphopenia decline might be directly induced by lymphocyte tissue destruction, inflammatory cytokines or metabolic disorder that caused by COVID-19 infection. TNF-alpha, IL-6, and other inflammatory cytokines could induce deficiency in lymphocytes.49\n\nNeutrophilia was also reported in this study, with a NLR of 7. In patients with COVID-19, NLR may reflect the severity of inflammation. Neutrophil percentages have been seen to be mostly within normal range in non-severe cases but were increased in severe form of illness.48 Elderly and critical patients tend to present with neutrophilia, and this condition is suggested to be related to the cytokine storm.50,51 A risk predictive model by Liu et al. suggested that incidence of severe disease was 50% in patients with an age 50 years or older and NLR greater or equal to 3.13 compared to 9.1% in patients with an age 50 years or older and NLR less than 3.13.52 In our study, subjects were >50 years and NLR >3.13, thus correlating with the risk of severe disease.\n\nInflammatory parameters (IL-6, IL-10, TNF-alpha, and IFN-gamma, MCP-1) were increased in COVID-19 patients with severe illness in this study. These findings were also found in recent studies.16,20,24,53,54 Patients with COVID-19 had high amounts of pro-inflammatory cytokines (IFN-gamma, TNF-alpha, IP-10, IL-1B, MCP-1). Patients requiring ICU admission had even higher number of cytokines, suggesting a cytokine storm was associated with progression of ARDS and severe illness. However, COVID-19 patients also present with increased anti-inflammatory cytokines (IL-4, IL-10), which differs from SARS-CoV infection.24,53 The Univariate Cox Analysis by Yang et al. indicated that circulating IL-6 significantly predicted the progression of COVID-19 infection. Serum IL-6 was higher in COVID-19 patients with pneumonia compared to those without pneumonia. Increased IL-6 might induce tissue-damaging-inflammation and cause alveolar cell injury.20 Patients with IL-6 greater than 32.1 pg/mL were more likely to have severe complications.16 IL-6 trans-signaling could enhance production of IL-8, MCP-1, and IL-10.54\n\nD-dimer also increased in our subjects, with a mean of 800 ng/mL. D-dimer is a fibrin degradation product widely used as a biomarker for thrombotic disorders. A D-dimer value less than 500 ng/mL is usually considered normal. D-dimer can predict severe and fatal cases of COVID-19 with moderate accuracy (sensitivity 77%, specificity 71%).55 In a multicentre meta-analysis by Paliogiannis et al., D-dimer concentrations in patients with severe COVID-19 are significantly higher when compared to those with non-severe forms.56 In the analysis by Ozen et al., threshold D-dimer value of 370 ng/ml was calculated to have 74% specificity and 77% sensitivity for predicting lung involvement in patients with COVID-19.57 A cut-off of 1,500 ng/mL is the optimal value of admission D-dimer for predicting mortality in COVID-19 patients.58\n\nCRP levels increased almost eightfold above reference values in this study. CRP is an active regulator of host innate immunity and induces the classical complement pathway, and is thereby capable of mediating inflammation.59 A significant increase of CRP was found in COVID-19 patients, with levels on average of 20 to 50 mg/L.60 CRP is normally not elevated in viral infections, but the macrophage activation syndrome may explain the high serum CRP and poorer disease progression. Elevated CRP may also indicate co-infections of bacterial etiology.61 Up to 86% of patients with a severe form of COVID-19 had increased CRP, in higher concentration compared to mild or non-severe patients.62 The risk of developing severe events is increased by 5% for every one-unit increase in CRP levels in COVID-19 patients.63\n\nThe mean level of lipase was significantly higher in men in our study. This finding was similar to the study by Barlass et al, who showed that increased lipase indicated possible inflammation of the pancreas and was connected with poor prognosis.64 Although there was higher lipase activity in the male animal model there was no definite explanation for higher activity of lipase in men.65 Lipase levels were also significantly different in the group of patients with and without comorbidities. After adjusted analysis with groups of comorbidities, there was no significant difference. Perhaps comorbidities could interfere with the body’s physiological processes and induce stress in various organs, including the pancreas.\n\nThis study has limitations because we don’t compare the laboratory profiles between severe groups and mild/moderate groups. However, for patients with COVID-19, the presence of comorbidities and elevated inflammatory markers should raise healthcare provider’s awareness for the risk of severe disease course. There are also interesting results that could be important for future treatment. Lipase, IL-6, and MCP-1 results were found significantly different between the vaccine and non-vaccine groups. Elevated lipase may indicate possible pancreatic involvement that may be a consideration in the management of COVID-19.\n\n\nData availability\n\nFigshare: COVID Master Data ICU.xlsx, https://doi.org/10.6084/m9.figshare.16823611.v2.66\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\nWHO Coronavirus (COVID-19) Dashboard: WHO Coronavirus (COVID-19) Dashboard With Vaccination Data.[cited 2021 Sep 28]. Reference Source\n\nGorbalenya AE, Baker SC, Baric RS, et al.: Severe acute respiratory syndrome-related coronavirus: The species and its viruses – a statement of the Coronavirus Study Group. bioRxiv. 2020 Feb 11 [cited 2021 Sep 28]; 2020.02.07.937862. Publisher Full Text\n\nWeekly epidemiological update on COVID-19-24 August 2021.[cited 2021 Sep 28]. Reference Source\n\nIndonesia: WHO Coronavirus Disease (COVID-19) Dashboard With Vaccination Data|WHO Coronavirus (COVID-19) Dashboard With Vaccination Data.[cited 2021 Sep 28]. Reference Source\n\nAlguwaihes AM, Al-Sofiani ME, Megdad M, et al.: Diabetes and Covid-19 among hospitalized patients in Saudi Arabia: a single-centre retrospective study. Cardiovasc. Diabetol. 2020 Dec 5 [cited 2021 Sep 28]; 19(1): 205–212. PubMed Abstract | Publisher Full Text\n\nMackenzie JS, Smith DW: COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and what we don’t. Microbiol Aust. 2020 Mar 1 [cited 2021 Sep 28]; 41(1): 45–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou F, Yu T, du R, et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England). 2020 Mar 28 [cited 2021 Sep 28]; 395(10229): 1054–1062. PubMed Abstract | Publisher Full Text\n\nHajjar LA, Costa IBS d S, Rizk SI, et al.: Intensive care management of patients with COVID-19: a practical approach. Ann. Intensive Care. 2021 Feb 18 [cited 2021 Sep 28]; 11(1): 36–17. PubMed Abstract | Publisher Full Text\n\nMatthay MA, Zemans RL, Zimmerman GA, et al.: Acute respiratory distress syndrome. Nat. Rev. Dis. Primers. 2019; 5(1): 18. 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PubMed Abstract | Publisher Full Text\n\nInnovation and Transformation in the Response to Covid-19: Seven Areas Where Clinicians Need to Lead|Catalyst non-issue content.[cited 2021 Sep 28]. Publisher Full Text\n\nLiu F, Li L, Xu M, et al.: Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J. Clin. Virol. 2020 Jun 1 [cited 2021 Sep 28]; 127: 104370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZumla A, Hui DS, Azhar EI, et al.: Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020 Feb 22 [cited 2021 Sep 28]; 395(10224): e35–e36. PubMed Abstract | Publisher Full Text Reference Source\n\nRamasamy S, Subbian S: Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis. Clin. Microbiol. Rev. 2021 Jul 1 [cited 2021 Sep 28]; 34(3). PubMed Abstract | Publisher Full Text | Free Full Text\n\nChannappanavar R, Perlman S: Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 2017 May 2 [cited 2021 Sep 28]; 39(5): 529–539. PubMed Abstract | Publisher Full Text\n\nYang P, Ding Y, Xu Z, et al.: Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. medRxiv. 2020 Mar 3 [cited 2021 Sep 28]; 2020.02.28.20028068. Publisher Full Text\n\nFalahi S, Kenarkoohi A: Sex and gender differences in the outcome of patients with COVID-19. J. Med. Virol. 2021 Jan 1 [cited 2021 Sep 28]; 93(1): 151–152. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDugail I, Amri E-Z, Vitale N: High prevalence for obesity in severe COVID-19: Possible links and perspectives towards patient stratification. Biochimie. 2020 Dec 1 [cited 2021 Sep 28]; 179: 257–265. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVaccine efficacy, effectiveness and protection: [cited 2021 Sep 28]. Reference Source\n\nYe Q, Wang B, Mao J: The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J. Infect. 2020 Jun 1 [cited 2021 Sep 28]; 80(6): 607–613. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNgai JC, Ko FW, Ng SS, et al.: The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology. 2010 Apr [cited 2021 Sep 28]; 15(3): 543–550. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected.[cited 2021 Nov 20]. Reference Source\n\nAppropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet (London, England). 2004 Jan 10 [cited 2021 Sep 28]; 363(9403): 157–163. PubMed Abstract | Publisher Full Text\n\nJin JM, Bai P, He W, et al.: Differences in patients with COVID-19: Focus on severity and mortality. Front. Public Health. 2020; 8: 152. PubMed Abstract | , PubMed Abstract | Publisher Full Text\n\nHaitao T, Vermunt JV, Abeykoon J, et al.: COVID-19 and Sex Differences: Mechanisms and Biomarkers. Mayo Clin. Proc. 2020 Oct 1 [cited 2021 Sep 28]; 95(10): 2189–2203. PubMed Abstract | Publisher Full Text\n\nSmoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015. Lancet (London, England). 2017 May 13 [cited 2021 Sep 28]; 389(10082): 1885–1906. PubMed Abstract | Publisher Full Text\n\nTukiainen T, Villani A-C, Yen A, et al.: Landscape of X chromosome inactivation across human tissues. Nat. 2017 Oct 12 [cited 2021 Sep 28]; 550(7675): 244–248. PubMed Abstract | Publisher Full Text Reference Source\n\nLucas JM, Heinlein C, Kim T, et al.: The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014 Nov 1 [cited 2021 Sep 28]; 4(11): 1310–1325. PubMed Abstract | Publisher Full Text\n\nWulandari L, Hamidah B, Pakpahan C, et al.: Initial study on TMPRSS2 p.Val160Met genetic variant in COVID-19 patients. Hum. Genomics. 2021 May 17 [cited 2021 Sep 28]; 15(1): 29–29. PubMed Abstract | Publisher Full Text\n\nHo FK, Petermann-Rocha F, Gray SR, et al.: Is older age associated with COVID-19 mortality in the absence of other risk factors? General population cohort study of 470,034 participants. PLoS One. 2020 Nov 1 [cited 2021 Sep 28]; 15(11): e0241824. PubMed Abstract | Publisher Full Text\n\nHu C, Li J, Xing X, et al.: The effect of age on the clinical and immune characteristics of critically ill patients with COVID-19: A preliminary report. PLoS One. 2021 Mar 1 [cited 2021 Sep 28]; 16(3): e0248675. PubMed Abstract | Publisher Full Text\n\nNeves MT, de Matos LV , Vasques AC, et al.: COVID-19 and aging: Identifying measures of severity.2021 Jun 24 [cited 2021 Sep 28]; 9: 205031212110274. Publisher Full Text PubMed Abstract |\n\nKompaniyets L, Goodman AB, Belay B, et al.: Body Mass Index and Risk for COVID-19–Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death — United States, March–December 2020. MMWR Surveill. Summ. 2021; 70(10): 355–361. Publisher Full Text\n\nKang IS, Kong KA: Body mass index and severity/fatality from coronavirus disease 2019: A nationwide epidemiological study in Korea. PLoS One. 2021 Jun 1 [cited 2021 Sep 28]; 16(6): e0253640. PubMed Abstract | Publisher Full Text\n\nStefan N, Birkenfeld AL, Schulze MB, et al.: Obesity and impaired metabolic health in patients with COVID-19. Nat. Rev. Endocrinol. 2020 Apr 23 [cited 2021 Sep 28]; 16(7): 341–342. PubMed Abstract | Publisher Full Text Reference Source\n\nJayanama K, Srichatrapimuk S, Thammavaranucupt K, et al.: The association between body mass index and severity of Coronavirus Disease 2019 (COVID-19): A cohort study. PLoS One. 2021 Feb 1 [cited 2021 Sep 28]; 16(2). PubMed Abstract | Publisher Full Text\n\nSanyaolu A, Okorie C, Marinkovic A, et al.: Comorbidity and its Impact on Patients with COVID-19. SN Compr Clin Med. 2020 Aug [cited 2021 Sep 28]; 2(8): 1069–1076. PubMed Abstract | Publisher Full Text\n\nCodo AC, Davanzo GG, Monteiro LB, et al.: Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis. Cell Metab. 2020 Sep 1 [cited 2021 Sep 28]; 32(3): 437–446.e5. PubMed Abstract\n\nLim S, Bae JH, Kwon H-S, et al.: COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat. Rev. Endocrinol. 2021 Jan 1 [cited 2021 Sep 28]; 17(1): 11–30. PubMed Abstract | Publisher Full Text\n\nSpeiser DE, Bachmann MF: COVID-19: Mechanisms of Vaccination and Immunity. Vaccine. 2020 Sep 1 [cited 2021 Sep 28]; 8(3): 1–22. PubMed Abstract | Publisher Full Text\n\nXi X, Guo Y, Zhu M, et al.: Higher expression of monocyte chemotactic protein 1 in mild COVID-19 patients might be correlated with inhibition of Type I IFN signaling. Virol. J. 2021 Jan 7 [cited 2021 Sep 28]; 18(1): 12–17. PubMed Abstract | Publisher Full Text\n\nPestka S, Krause CD, Walter MR: Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 2004 Dec [cited 2021 Sep 28]; 202: 8–32. PubMed Abstract | Publisher Full Text\n\nHuang G, Kovalic AJ, Graber CJ: Prognostic Value of Leukocytosis and Lymphopenia for Coronavirus Disease Severity. Emerg. Infect. Dis. 2020 Aug 1 [cited 2021 Sep 28]; 26(8): 1839–1841. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhartabil TA, Russcher H, van der Ven A , de Rijke YB : A summary of the diagnostic and prognostic value of hemocytometry markers in COVID-19 patients.2020 Aug 17 [cited 2021 Sep 28]; 57(6): 415–31. Publisher Full Text\n\nTan L, Wang Q, Zhang D, et al.: Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct. Target. Ther. 2020 Mar 27 [cited 2021 Sep 28]; 5(1): 1–3. Publisher Full Text Reference Source\n\nLin Y, Ji C, Weng W, et al.: Epidemiological and Clinical Characteristics of 124 Elderly Outpatients with COVID-19 in Wuhan, China. SSRN Electron. J. 2020 Feb 20 [cited 2021 Sep 28]. Publisher Full Text Reference Source\n\nHu L, Chen S, Fu Y, et al.: Risk Factors Associated With Clinical Outcomes in 323 Coronavirus Disease 2019 (COVID-19) Hospitalized Patients in Wuhan, China. Clin. Infect. Dis. 2020 Nov 19 [cited 2021 Sep 28]; 71(16): 2089–2098. PubMed Abstract | Publisher Full Text Reference Source\n\nLiu J, Liu Y, Xiang P, et al.: Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J. Transl. Med. 2020 May 20 [cited 2021 Sep 28]; 18(1): 206. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang C, Wang Y, Li X, et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15 [cited 2021 Sep 28]; 395(10223): 497–506. Publisher Full Text hReference Source\n\nSingh S, Anshita D, Ravichandiran V: MCP-1: Function, regulation, and involvement in disease. Int. Immunopharmacol. 2021 [cited 2021 Sep 28]; 107598. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhan H, Chen H, Liu C, et al.: Diagnostic Value of D-Dimer in COVID-19: A Meta-Analysis and Meta-Regression.2021 Apr 29 [cited 2021 Sep 28]; 27. Publisher Full Text\n\nPaliogiannis P, Mangoni AA, Dettori P, et al.: D-Dimer Concentrations and COVID-19 Severity: A Systematic Review and Meta-Analysis. Front. Public Health. 2020 Jan 1; 8: 432. Publisher Full Text\n\nOzen M, Yilmaz A, Cakmak V, et al.: D-Dimer as a potential biomarker for disease severity in COVID-19. Am. J. Emerg. Med. 2021 Feb 1 [cited 2021 Sep 28]; 40: 55–59. Publisher Full Text Reference Source\n\nPoudel A, Poudel Y, Adhikari A, et al.: D-dimer as a biomarker for assessment of COVID-19 prognosis: D-dimer levels on admission and its role in predicting disease outcome in hospitalized patients with COVID-19. Ai T, editor. PLoS One. 2021 Aug 26 [cited 2021 Sep 28]; 16(8): e0256744. PubMed Abstract | Publisher Full Text\n\nPepys MB: C-reactive protein predicts outcome in COVID-19: is it also a therapeutic target?. Eur. Heart J. 2021 Jun 14 [cited 2021 Sep 28]; 42(23): 2280–2283. PubMed Abstract | Publisher Full Text Reference Source\n\nAli N: Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19. J. Med. Virol. 2020 Nov 1 [cited 2021 Sep 28]; 92(11): 2409–2411. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLuan Y, Yin C, Yao Y: Update Advances on C-Reactive Protein in COVID-19 and Other Viral Infections. Front. Immunol. 2021 Aug 10; 12: 3153. Publisher Full Text\n\nMo P, Xing Y, Xiao Y, et al.: Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin. Infect. Dis. An Off. Publ. Infect. Dis. Soc. Am. 2020 Mar 16 [cited 2021 Sep 28]. Free Full Text\n\nWang G, Wu C, Zhang Q, et al.: C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation. Open Forum Infect. Dis. 2020 May 1 [cited 2021 Sep 28]; 7(5). PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarlass U, Wiliams B, Dhana K, et al.: Marked Elevation of Lipase in COVID-19 Disease: A Cohort Study. Clin. Transl. Gastroenterol. 2020 [cited 2021 Sep 28]; 11(7): e00215. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThongprajukaew K, Kovitvadhi U: Effects of sex on characteristics and expression levels of digestive enzymes in the adult guppy poecilia reticulata. Zool. Stud. 2013; 52(1). Publisher Full Text\n\nPakpahan C: COVID Master Data ICU.xlsx. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "102157",
"date": "21 Dec 2021",
"name": "Kurnia Fitri Jamil",
"expertise": [
"Reviewer Expertise Tropical disease and infection",
"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\nThe suggestions that we can give to the manuscript are:\nThe grammatical errors in the text were quite large in number. Authors need to send the manuscript for proofreading and correction.\n\nAs highlighted by the authors, the time of study was short.\n\nIt is better if the authors can provide more updates or additional facts that can be obtained from this study compared to what has already been published in the literature.\n\nI suggest that the inflammation laboratory findings, especially C-reactive protein, are compared when the patient is admitted to the hospital and at the end of the treatment, and differentiated by each stage of COVID-19 disease.\n\nReferences: Correct or full citation for reference numbers 2, 15, 20, 36, 50, 54, 62.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7657",
"date": "05 Jan 2022",
"name": "Cennikon Pakpahan",
"role": "Author Response",
"response": "1. In response to the reviewer’s comments, we have sent and revised the manuscript according to Enago English Editing and Proofreading Services. 2. Thank You for your valuable comment. We conducted a cross-sectional study to explore the inflammatory profile of severe COVID-10 patients. Hence, we only involved looking at data from COVID-19 cases admitted to the ICU of Mitra Medica General Hospital Medan at one specific point in time (between May and June 2021). 3. We thank your reviewer’s suggestion. During our research and writing the manuscript, there are not many studies had reported on inflammatory parameters, enzymes, and COVID-19 prognosis. We cited new findings, such as the inflammatory profile of severe COVID-19 patients with or without vaccination. We think these things are new facts regarding COVID-19 management. 4. Thank you for the interesting comment. We apologize for not presenting these data, because, in the beginning, we did not design the study to compare the inflammatory profile between the degrees of COVID-19. We only aimed to explore the profile of inflammation parameters in the severe group with various variables. We have described this in the limitation of the study in the last paragraph. 5. Once again thank you for your comment. We have rechecked for references consistency carefully."
}
]
},
{
"id": "102162",
"date": "04 Jan 2022",
"name": "Intan Mauli Warma Dewi",
"expertise": [
"Reviewer Expertise Microbiology and 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\nWith interest, I read the study entitled “Inflammatory laboratory findings associated with severe illness among hospitalized individuals with COVID-19 in Medan, Indonesia: a cross-sectional study” by Darmadi et.al. In this study, the authors present the clinical and inflammatory characteristics of critically ill COVID-19 patients in the ICU. The results highlight the increased inflammatory profiles in severe COVID-19 patients and in those with comorbidities. Please find some minor comments below:\nIn the method section, the authors mentioned that among data collected was “vaccination status”. Please elaborate whether this refers to COVID-19 vaccination (or others).\n\nIn the results, clinical and laboratory parameters were compared to normal reference values. Do these values represent the population where the study was performed (i.e. Indonesian?) In this case, ideally, samples measured from healthy controls and/or patients with milder disease should be included in the study to provide a better comparison.\n\nIn table 3, the authors compared inflammatory marker levels in patients with different BMI categories and showed no significant differences between the groups. Did the author also look at the correlation between the BMI values and levels of these markers to further justify this finding?\n\nFigure 2 shows the comparison of laboratory parameters between the non-comorbid and comorbid groups. However, in this study, the assessed comorbidities have completely different mechanisms, and hence, characteristics (for example, those with pulmonary diseases such as COPD or tuberculosis, those with CKD, and those with metabolic or cardiovascular diseases would have different immune background). Can the authors justify why in figure 2 the comorbidities were categorized into one entity and not analyzed as separate?\n\nIn figure 3, is the duration post-vaccination (I would assume COVID-19 vaccination?) and numbers of vaccines known? Please elaborate in the methods section.\n\nIn the methods section, the authors only mentioned that samples were collected after 24 hours of ICU admission. Is the duration of illness known? The authors should add this in the methods section, or elaborate in the discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? 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": "7678",
"date": "11 Jan 2022",
"name": "Cennikon Pakpahan",
"role": "Author Response",
"response": "1. Thank you for the clarification. Vaccination status refers to COVID-19 vaccination; we have added this in the latest revision. 2. We apologize for providing ambiguous information. The normal reference values in the table are the normal reference values used by the laboratory during the examination. 3. Thank you for providing interesting input on our article. We've determined the statistical tests (disease type and lab parameters) and it was an insignificant correlation with all inflammation parameters (p>0.05). We include the statistical results in the supplementary data. We just presented statistically significant data to address our study. 4. We thank you for your opinion. At the beginning of the study, we conducted this test. However, we found no significant results between the comorbid and inflammatory parameters. Then we tried to group all types of comorbidity into one group and compared with no comorbidity. From this test, several significant parameters were obtained. We include the statistical results of this test in the supplementary data. 5. We recognize that this information is essential. However, many patients who enter our hospital are in poor condition, so we do not get factual information about this. We decided not to include this in the study to prevent recall bias. 6. Once again, thank you very much for your opinion. The problem we found with this information was that some of our research samples were in poor condition, not worthy of being asked for information. To prevent recall bias, we decided not to include it."
},
{
"c_id": "7729",
"date": "19 Jan 2022",
"name": "Intan Dewi",
"role": "Reviewer Response",
"response": "The authors have sufficiently addressed the comments. I have no further comments on the revised version of the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1246
|
https://f1000research.com/articles/11-44/v1
|
13 Jan 22
|
{
"type": "Research Article",
"title": "Ultrasound findings in lateral elbow tendinopathy: A retrospective analysis of radiological tendon features",
"authors": [
"Guillermo Droppelmann",
"Felipe Feijoo",
"Cristobal Greene",
"Manuel Tello",
"Julio Rosales",
"Roberto Yáñez",
"Carlos Jorquera",
"David Prieto",
"Felipe Feijoo",
"Cristobal Greene",
"Manuel Tello",
"Julio Rosales",
"Roberto Yáñez",
"Carlos Jorquera",
"David Prieto"
],
"abstract": "Background: Lateral elbow tendinopathy (LET) is prevalent in the upper extremity, with various therapeutic options. Understanding the types and the relations between the radiological tendon features would help to develop more specific treatments. This study reviewed ultrasound exams of LET to investigate the types of degenerative findings and the relationships between them in one of the most prominent sports medicine clinics in Latin America. Methods: A retrospective study was performed. We evaluated 4335 ultrasonographic exams with LET from 2017 and 2018. Five principal degenerative ultrasound criteria with subtypes were selected: hypoechogenicity, neovascularity, calcification, enthesopathy, and intrasubstance tear. A multiple linear regression model was conducted to explore the association between the findings, sex, and age. Results: Overall, 4324 ultrasound exams were analyzed; 2607 (60.29%) were males. Multiple degenerative tendon findings were found in adults (≥18 years) with LET. Hypoechogenicity (67.77%) and neovascularity (37.8%) were the most frequent. The mean length of a tendon tear in both sexes was 4.44 (± 2.81) millimeters. Mild hypoechogenicity (P < .001), and depth intrasubstance tear (P < .01) were statistically significant between them. Severe hypoechogenicity was associated with an increase in all tendon tear dimensions for length 1.37 ([95% Confidence interval (CI), 0.57, 2.17]; P < .001), for width 1.10 ([95% CI, 0.33, 1.87]; P < .01) and for depth 1.64 ([95% CI, 0.40, 2.88]; P < .01). Additional findings associated with an increase in the length dimension were 0.42 associated with focal neovascularity ([95% CI, 0.19, 0.65]; P < .001), and 0.71 associated with multiple neovascularity ([95% CI, 0.27, 1.15]; P < .01). Conclusions: Hypoechogenicity and neovascularity findings presented a positive association with the size of tendon tear in patients with LET. This study reaffirms the increased predominance of tendon tear during the 4th to 6th decades of life.",
"keywords": [
"Extensor carpi radialis brevis",
"tendon tear",
"tennis elbow",
"ultrasound."
],
"content": "Introduction\n\nTendinopathies are a crucial global burden of musculoskeletal disorders.1 Specifically, lateral elbow tendinopathy (LET), or tennis elbow,2 is one of the most prevalent degenerative conditions in the upper extremity.3 It has been shown that LET affects both sexes, between 35 to 54 years4 with severe pain,5 and functional disability in wrist extension and handgrip activities.6,7 The LET symptoms can persist for more than 12 months,8 directly impacting a patient’s quality of life,9 sports activities,10 occupational settings11 and the health system.12\n\nThe LET pathogeneses are similar to other tendinopathies. These includes collagen disorganization, neurovascular ingrowth,13 tissue necrosis with myxoid and hyaline degeneration and fibrosis.14 Most of the degenerative process is concentrated on the extensor carpi radialis brevis (ECRB) tendon.15,16 These histological changes were first described in 1979.17 In 2009, two researchers proposed an alternative model to describe continuous tendon changes based on three states of its structure: reactive, disrepair and degenerative.18 Additionally, in 2016, another investigation included a final phase with gross structural disruption and tendon tear.19\n\nThese structural tendon changes can be identified with imaging methods,20 ultrasound (US) findings in the degenerative stage has been well documented21 and can be a useful tool to detect signs such as hypoechoic areas, neovascularization, calcifications, enthesopathy, and intrasubstance tears22 with better sensitivity and accuracy than magnetic resonance imaging (MRI).23,24\n\nIn this context, there is no consensus in the literature about the main ultrasound findings in LET. For example, a study evaluated 240 patients with this condition with the highlighted presence of calcifications,25 but another article identified hypoechoic areas, partial and total tears principally.26\n\nCurrently, articles have been published with standardized graduations of US findings, allowing to subclassify the magnitude of the tendon’s structural changes.21,27 For instance, hypoechogenicity and hyperemia have been divided in severity values of 0% to 30%, between 30 to 50% and more than 50%.28 Intrasubstance tears of the tendon have also been added.29 However, the dimensions and magnitudes have not yet been specified.22 Still, most of the articles have reported individual degenerative tendon characteristics without studying the relationship and occurrence of more than one degenerative characteristic simultaneously. And this is vital because abnormalities in the tendon structure are considered a risk factor for developing symptoms of LET.30 For example, an author suggested vascular in-growth into tendons may be the cause of tendon weakness and tears.31 Another article confirmed that 97% of tendon tears have degenerative changes.32 More recently, a meta-analysis indicated that there was a higher relative risk for developing clinical tendinopathy when multiple US findings were considered.33\n\nWe know that the tendon tear is the final phase of the degenerative process in this tissue and the number of US findings could determine the severity of the tendinopathy. However, the frequency of degenerative findings, the size of tendon tears, and the association between them in LET are poorly known. Indeed, to date, no studies have investigated the types of degenerative findings and the relationships between them. Hence the main aim of this study was to identify the frequency and evaluate associations between standardized degenerative tendon findings with tendon tears in three sizes dimensions (length, width, and depth). This is a unique study with one of the most extensive collections of ultrasound exams analyzed to the best of the authors' knowledge.\n\n\nMethods\n\nThis study has been performed in keeping with the latest version of the Declaration of Helsinki, in accordance with Chilean legislation. The study was approved by the Comité de Ética Científico Adulto del Servicio Metropolitano Oriente de la ciudad de Santiago de Chile (SSMO). The ethical committee required no informed consent from patients given the retrospective nature of the study. The project was approved on August 17, 2018. No approval number was recorded.\n\nThis research was designed as a descriptive, retrospective, multicentric study and was written in accordance to the Strengthening the Reporting of Observation studies in Epidemiology (STROBE) guideline.34 This study started on January 14, 2019. All patients with documentation of elbow ultrasound at MEDS Clinic in Santiago, Región Metropolitana, Chile, from January 1, 2017, to December 31, 2018, were selected for the study. The included patients had LET suspicion with any unilateral or bilateral signs or symptoms in this period. If the patient had multiple episodes of LET at different times, each episode was included. Our Medical Imaging Software (Carestream RIS, v.11) allows a word search of the whole electronic ultrasound exams record database between 2017 to 2018. Authors GD, FF, and MT had access to the database. Any structural tendon change of all the patients with exams of any search containing the word LET were included. The exams were diagnosed by five musculoskeletal radiologists with more than ten years of experience. Of these, only JR was an author of this article. The professionals used an Aplio 500 US system (Toshiba America Medical Systems, Inc, Tustin, CA) equipped with a multifrequency linear transducer with a frequency of 18 MHz to inform the LET condition. Demographics such as sex, age, and size of the injury were recorded. The exams with a history of musculoskeletal ultrasound guided treatment, such as injections, or any surgery, were excluded from the analysis. Physical activity, pain score, and time of symptoms were not reported.\n\nWe proposed a standardized categorization to assess the presence of five principal US criteria with subdivisions based on previous reports in the literature.16,21,26,35,36 A normal tendon was defined as no changes in the tendon structure. Hypoechogenicity was defined as being rounded and not associated with tendon disruption and was evaluated depending on the tendon extension structure, with an ordinal score from 0 to 3, with 0 representing a normal tendon echogenicity, mild level (HE1) is 1% to 30%, moderate level (HE2) is 31% to 50% and severe level (HE3) is over 50%. Neovascularity was assessed with the maximum number of color pixels occupying the tendon origin, an ordinal score from 0 to 2, where 0 represents no neovascularity presence, 1 represents focal neovascularity (NV1) with 30% blood vessels, and 2 refers to multiple neovascularity (NV2) consisting of more than 31% blood vessels. A linear intrasubstance tear was defined as a linear hypoechoic focus associated with discontinuity of tendon fibers. The number of tendon tears was recorded as a focal intrasubstance tear (IST1) or multiple intrasubstance tear (IST2). The size of the abnormality was measured in millimeters. The site of the abnormality was examined in two planes and assigned as predominantly affecting the superficial, mid, or deep fibers and the anterior, mid, or posterior fibers. Calcification (C) was defined as calcium deposits in the substance of the tendon and enthesopathy (E) was defined as the pathologies that affect the entheses. Both findings were categorized as a binary score (absent and present).\n\nData was reported with frequencies, means, and standard deviations (SD), when corresponding. The Chi-square test was used to compare categorical data and T-test for continuous variables. Univariate comparisons between the tear’s size in each dimension and degenerative findings were performed using the Kruskal Wallis test. A separate multiple linear regression model was fit to analyze the association between sex, age, and degenerative findings with tendon tear in each dimension (length, width, and depth).\n\nNeither final exposure variables nor outcome data presented missing values. Missing data analysis showed that missingness were at random; multivariate regression imputation was employed as required. P value < .05 was considered a statistically significant, two-tailed statistics were used. All graphs and analyses were performed using R (The R Foundation for Statistical Computing, v. 3.6.2) and (RStudio, v.4.1.0).\n\n\nResults\n\nA total of 4335 US exams from 2926 patients with suspicion of LET were included in our analysis. Of these, 11 exams were excluded as they did not present any final report. Summary data from ultrasonographic exams are available in Underlying data.45 The age of patients with LET presented a minimum value of 18 years and a maximum of 91 years. The data shows that women have a mean age 47.18 ±11.00 (P < .001), and are on average, one year older than males. In 70% of the patients, the affected side was the right elbow.\n\nThe HE1 was the most frequent structural change detected on US (53.07%), followed by enthesopathy (35.01%), focal neovascularity (33.55%), and focal intrasubstance tear (31.91%). However, when the results considered the subtypes classification, the frequency distribution changed. Frequency (number of cases diagnosed) for most of the degenerative findings were very similar between females and males. More than a third of exams with LET showed an intrasubstance tear in the tendon, see Table 1.\n\na Values are presented as mean ±SD or No. (%). HE0, no hypoechogenicity; HE1, mild hypoechogenicity; HE2, moderate hypoechogenicity; HE3, severe hypoechogenicity; NV0, no neovascularity; NV1, focal neovascularity; NV2, multiple neovascularity; ISR0, no intrasubstance tear; IST1, focal intrasubstance tear; IST2, multiple intrasubstance tear; C0, no calcification; C, calcification; E0, no enthesopathy; E, enthesopathy.\n\nb Statistical significance between the groups, P < .05.\n\nAdditionally, men with focal and multiple intrasubstance tears, in all three dimensions (length, width, depth), presented a larger tear size than women. Overall, the variables age (P < .001), HE1 (P < .001), and depth IST1 (P < .01) were statistically significant between females and males. A synthesis is provided in Table 1.\n\nThe category of hypoechogenicity depends on the size of the intrasubstance tear. The length compared with width and depth dimensions presented the most significant variability among hypoechogenicity levels. Also, an increase in the median length of the tear occurs when the tendon presented higher levels of hypoechogenicity (HE3).\n\nParticularly, Figure 1 shows that the length of the tear for HE3 cases, when compared with HE2, is significantly different (P = .035). Nevertheless, when the width of the tendon tear and different levels of hypoechogenicity were considered, the biggest difference (P < .001) occurred between HE1 to HE2 (not shown in the figure).\n\nThe highest hypoechogenicity levels show the most length of intrasubstance tear. HE0, no hypoechogenicity; HE1, mild hypoechogenicity; HE2, moderate hypoechogenicity; HE3, severe hypoechogenicity.\n\nSimilarly, in Figure 2, we show the relationship for the width dimension of tendon tear with the presence of two neovascularity levels (NV1 and NV2). Again, higher values of width tear dimensions were associated with the presence of the greater neovascularity level (P < .005). However, only NV0 to NV1 transitions demonstrated a significant difference (P < .004). Something similar happened with the depth of tear. This case did not show statistically significant differences among neovascularity levels. This may be due to the low frequency of cases in the deep dimension (not shown in figure).\n\nVascularity presence shows higher values of width tear. NV0, no neovascularity; NV1, focal neovascularity; NV2, multiple neovascularity.\n\nFinally, Figure 3 shows that the depth dimension presented the highest statistical difference (P = .007) between HE0 and HE1, with no essential differences among hypoechogenicity HE1 and HE2 levels. Also, HE2 compared to HE3 shows statistical significance (P = .025). However, the number of cases with depth tear and HE3 is deficient, hence it might not be representative.\n\nHypoechogenicity presence could influence the depth of intrasubstance tear. HE0, no hypoechogenicity; HE1, mild hypoechogenicity; HE2, moderate hypoechogenicity; HE3, severe hypoechogenicity.\n\nSubsequently, we examined if the three dimensions of tendon tear presented statistical differences with the presence of other degenerative findings. We performed linear regression models for each tear dimension as shown in Table 2. Hypoechogenicity had an effect in all tendon tear dimensions with an average increase from H0 to H3 of 1.37 ([95% CI, 0.57, 2.17]; P < .001) in length, of 1.10 ([95% CI, 0.33, 1.87]; P < .01) in width and of 1.64 ([95% CI, 0.40, 2.88]; P < .01) in depth. For the length dimension, neovascularity showed and average increase of 0.42 ([95% CI, 0.19, 0.65]; P < .001) and multiple neovascularity of 0.71 ([95% CI, 0.27, 1.15]; P < .01). Enthesopathy reduced the average width by -0.37 ([95% CI, -0.62, -0.13]; P < .01) and increased the average width by 0.57 ([95% CI, 0.19, 0.95]; P < .01) respectively.\n\na Values are presented No. (%) and estimated coefficients (95% confidence intervals); HE0, no hypoechogenicity; HE1, mild hypoechogenicity; HE2, moderate hypoechogenicity; HE3, severe hypoechogenicity; NV0, no neovascularity; NV1, focal neovascularity; NV2, multiple neovascularity; C0, no calcification; C, calcification; E0, no enthesopathy; E, enthesopathy;\n\n* , Comparator;\n\nb Statistical significance between the groups, P < .05.\n\nFor practically all the dimensions, neovascularity and both moderate and severe hypoechogenicity findings presented positive coefficients. The higher the presence of these findings, the greater the size of the tear. However, the presence of calcifications and enthesopathy are mostly associated with a decrease in the size of the tear.\n\nWe found that the size of tendon tear, for all three dimensions, increased with age. Patients above 60 years show higher length tendon tear 0.88 ([95% CI, 0.40, 1.35]; P < .001) and width tendon tear 0.61 ([95% CI, 0.09, 1.14]; P < .05) both with significant p-values. Although male patients have an increased size of tear in all dimensions compared to women, this was only barely significant in the depth of the tear 0.32 ([95% CI, 0.00, 0.65]: P < .05). Note that patients in age-groups 0-20 and over 81 years old did not present tendon tear.\n\nFinally, it was evaluated whether interactions between the exposure variables could improve the models in any of the three proposed dimensions of tendon tear. However, none of the interactions among the different types of degenerative findings presented statistical significance.\n\n\nDiscussion\n\nThe presence of tendinopathies is a frequent problem for the general population and athletes. Notably, LET is the most commonly diagnosed elbow musculoskeletal disorder and still represents an unresolved problem for public health.37 Multiple studies have discussed the structural changes that can be found exclusively in LET such as tissue thickening, hypoechoic areas, neovascularization areas, fibrillary disruption, and bone abnormalities.21,26,34 As demonstrated in this research, it is infrequent that the degenerative findings are present in isolation and unrelated. Our study allows us to determine the presence of four large groups of degenerative findings and the presence of gradual lesions, which can determine the presence of tear within the tendon.\n\nIn a large sample of ultrasounds exams obtained over two years, our analysis indicates that the age and tendon degenerative findings of patients were the most critical factors associated with increased tendon tear in any dimension. Particularly, we found a positive relationship between the presence of hypoechogenicity levels and the length of tear and neovascularity levels with the tear width. This result suggests that if the goal is to reduce the magnitude and the variability of tendon tear in patients with LET, hypoechogenicity, and neovascularity should influence the importance of degenerative findings, so preventive ultrasound exams could be useful to avoid potential tendon tears.38 Furthermore, this information can be used to assess lateral elbow tendinopathy severity. For example, investigators concluded that the size of intrasubstance tear on an ultrasound could determine which patients respond to nonoperative treatment and the correlation with functional disability.39 However, the tendon tear description did not include the magnitude of the tear dimension, HE, and NV findings. Therefore, it is essential to have this information in future studies.\n\nOn the other hand, there are several possible explanations for the positive association of hypoechogenicity and neovascularity with the dimension of the tendon tear. Firstly, the ECRB is the central tendon involved in a degenerative process of LET, and in this study, we only considered the exhaustive descriptions and analysis for degenerative ultrasound findings in the interior of this tendon. However, most of the existing publications describe the relation between LET and different anatomical aspects40 or other adjacent tissues such as nerve, ligaments, muscles, bone structures or more tendons41 and even other health conditions that are not unique to the alteration of the origin of the wrist extensors.\n\nSecondly, researchers have proposed that the tendon pathogenesis model is continuous, arguing that there is a 3-state transition from an initial stage characterized by reactive tendinopathy, a second disruptive stage, and finally, a third degenerative stage.42 We believe that this last stage also presents graduation, particularly with some degenerative findings because they can be subdivided according to their degree of commitment. Furthermore, the existence of the demonstrated associations could support future predictive models that determine whether the existence of one finding anticipates the appearance of another.\n\nRecently, a study showed that LET primarily affects middle-aged people43 and that the probability of having LET decreases with older age.12 Our study shows that age is strongly associated with the tendon tear's size, so the older the patient, the higher the magnitude of the tear independent of the dimension evaluated. The results confirm that men have LET almost a year earlier than women. However, the clinical importance lies in identifying the tendons' structural characteristics using ultrasound.\n\nSome authors even propose that US examinations be performed even in subjects who do not present symptoms but could present degenerative findings.27 As we could observe in our study, the degenerative findings could present graduations before the tendon tear, so earlier identification of these findings would allow monitoring future tendon tears and could improve the therapeutic resolution capacity. It is important to have future publications that can assign a time factor to degenerative findings to understand the natural evolution of such tendon tear.\n\nThe study's principal limitation was the retrospective design, which is often considered inferior to prospective, randomized, and controlled clinical trials.44 Additionally, we couldn't manage the imaging procedure and settings, and inter and intra rater reliability was not considered, losing external validity. Further limitations include assessment only of ECRB tendon, hindering results generalization. However, this is the study with the highest number of exams analyzed to the best of the authors' knowledge. An additional limitation was that the images correspond to patients with different conservative treatments, pain scores, evolution times, physical activity levels, comorbidities, and clinical manifestations. This study focused solely on the characteristics of ultrasound exams, not incorporating these elements. Future studies should consider a cohort design to assess these considerations.\n\n\nConclusions\n\nIn summary, this study provides evidence of a positive association between the presence of hypoechogenicity and neovascularity findings with the increased size of a tendon tear in patients with LET. Additionally, we reaffirm the higher frequency of tendon tears between 40 to 60 years of age but a greater magnitude of the injury from 60 years of age. This article demonstrates the importance of degenerative findings in the magnitude of tendon injury.\n\n\nData availability\n\nThe ultrasonographic exams are not available publicly because consent for publication of raw data was not obtained, and the dataset could pose a threat to confidentiality. Researchers and reviewers interested in accessing the data will need to submit an official request letter to the Academic Unit, MEDS Clinic. They must also confirm that they will not violate the ethical standards of the ethical committee and protect the anonymity of the participants. Interested parties can contact the corresponding author, Guillermo Droppelmann (guillermo.droppelmann@meds.cl) who can facilitate this process.\n\nFigshare: Ultrasound findings in lateral elbow tendinopathy. https://doi.org/10.6084/m9.figshare.16713427.v445\n\nThis project contains the following underlying data:\n\n- LET - data.xlsx (summary data from ultrasonographic exams).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe are grateful for the kind collaboration and assistance of the Sports Medicine Data Science Center MEDS-PUCV and the Harvard T.H. Chan School of Public Health during this process. Special thanks to Dr. Nicolás García from the Department of Radiology, Clínica MEDS.\n\n\nReferences\n\nHoy DG, Smith E, Cross M, et al.: The global burden of musculoskeletal conditions for 2010: An overview of methods. Ann. Rheum. Dis. 2014; 73: 982–989. PubMed Abstract | Publisher Full Text\n\nVerhaar JAN: Tennis elbow - Anatomical, epidemiological and therapeutic aspects. Int. Orthop. 1994; 18. Publisher Full Text\n\nShiri R, Viikari-Juntura E, Varonen H, et al.: Prevalence and determinants of lateral and medial epicondylitis: a population study. Am. J. Epidemiol. 2006; 164(11): 1065–1074. PubMed Abstract | Publisher Full Text\n\nHamilton PG: The prevalence of humeral epicondylitis: a survey in general practice. J. R. Coll. Gen. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nKraushaar BS, Nirschl RP: Tendinosis of the elbow (Tennis elbow): Clinical features and findings of histological, immunohistochemical, and electron microscopy studies. Journal of Bone and Joint Surgery American and British volumes (CD-ROM). 1999; 81: 259–278. PubMed Abstract | Publisher Full Text\n\nChard MD, Cawston TE, Riley GP, et al.: Rotator cuff degeneration and lateral epicondylitis: a comparative histological study. Ann. Rheum. Dis. 1994; 53: 30–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDones VC, Grimmer K, Thoirs K, et al.: The diagnostic validity of musculoskeletal ultrasound in lateral epicondylalgia: a systematic review. BMC Med. Imaging. 2014; 14PubMed Abstract | Publisher Full Text | Free Full Text\n\nVaquero-Picado A, Barco R, Antuña SA: Lateral epicondylitis of the elbow. EFORT Open Rev. 2016; 1: 391–397. 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Radiology. 2005; 237: 230–234. PubMed Abstract | Publisher Full Text\n\nPoltawski L, Ali S, Jayaram V, et al.: Reliability of sonographic assessment of tendinopathy in tennis elbow. Skelet. Radiol. 2012; 41: 83–89. PubMed Abstract | Publisher Full Text\n\nWestacott DJ, Minns JI, Foguet P: The diagnostic accuracy of magnetic resonance imaging and ultrasonography in gluteal tendon tears - a systematic review. HIP Int. 2011; 21: 637–645. PubMed Abstract | Publisher Full Text\n\nWarden SJ, Kiss ZS, Malara FA, et al.: Comparative accuracy of magnetic resonance imaging and ultrasonography in confirming clinically diagnosed patellar tendinopathy. Am. J. Sports Med. 2007; 35: 427–436. PubMed Abstract | Publisher Full Text\n\nJaén-Díaz JI, Cerezo-López E, López-de Castro F, et al.: Sonographic findings for the common extensor tendon of the elbow in the general population. J. Ultrasound Med. 2010; 29: 1717–1724. PubMed Abstract | Publisher Full Text\n\nConnell D, Burke F, Coombes P, et al.: Sonographic examination of lateral epicondylitis. Am. J. Roentgenol. 2001; 176: 777–782. PubMed Abstract | Publisher Full Text\n\nKrogh TP, Fredberg U, Ammitzbøl C, et al.: Ultrasonographic characteristics of the common extensor tendon of the elbow in asymptomatic individuals: Thickness, color doppler activity, and bony spurs. Orthop. J. Sports Med. 2017; 5: 232596711770418. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPalaniswamy V, Ng SK, Manickaraj N, et al.: Relationship between ultrasound detected tendon abnormalities, and sensory and clinical characteristics in people with chronic lateral epicondylalgia. PLoS One. 2018; 13: e0205171. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBachta A, Rowicki K, Kisiel B, et al.: Ultrasonography versus magnetic resonance imaging in detecting and grading common extensor tendon tear in chronic lateral epicondylitis. PLoS One. 2017; 12: e0181828. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcAuliffe S, McCreesh K, Culloty F, et al.: Can ultrasound imaging predict the development of Achilles and patellar tendinopathy? A systematic review and meta-analysis. Br. J. Sports Med. 2016; 50: 1516–1523. PubMed Abstract | Publisher Full Text\n\nPufe T, Petersen WJ, Mentlein R, et al.: The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease. Scand. J. Med. Sci. Sports. 2005; 15: 211–222. PubMed Abstract | Publisher Full Text\n\nKannus P, Jozsa L: Histopathological changes preceding spontaneous rupture of a tendon: A controlled study of 891 patients. J. Bone Jt. Surg. - Ser. A. 1991; 73: 1507–1525. PubMed Abstract | Publisher Full Text\n\nMatthews W, Ellis R, Furness J, et al.: Classification of Tendon Matrix Change Using Ultrasound Imaging: A Systematic Review and Meta-analysis. Ultrasound Med. Biol. 2018; 44: 2059–2080. PubMed Abstract | Publisher Full Text\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 Oct; 4(10): e297. [cited 2021 Oct 19]. Publisher Full Text\n\nCoombes BK, Bisset L, Vicenzino B: Management of lateral elbow tendinopathy: One size does not fit all. J. Orthop. Sports Phys. Ther. 2015; 45: 938–949. Publisher Full Text\n\nOliva F, Via AG, Maffulli N: Physiopathology of intratendinous calcific deposition. BMC Med. 2012 Aug 23; 10: 95. [cited 2021 Oct 21]. Publisher Full Text | Free Full Text\n\nSakabe T, Sakai T: Musculoskeletal diseasestendon. Br. Med. Bull. 2011; 99: 211–225. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHeales LJ, Broadhurst N, Mellor R, et al.: Diagnostic ultrasound imaging for lateral epicondylalgia: A case-control study. Med. Sci. Sports Exerc. 2014; 46(11): 2070–2076.\n\nClarke AW, Ahmad M, Curtis M, et al.: Lateral elbow tendinopathy: Correlation of ultrasound findings with pain and functional disability. Am. J. Sports Med. 2010; 38: 1209–1214. PubMed Abstract | Publisher Full Text\n\nGoldie I: Epicondylitis Lateralis Humeri (Epicondylalgia or Tennis Elbow). A Pathogenetical Study. Acta Chir. Scand. Suppl. 1964.\n\nObuchowicz R, Bonczar M: Ultrasonographic Differentiation of Lateral Elbow Pain. Ultrasound Int. Open. 2016; 02: E38–E46. Publisher Full Text\n\nMccreesh K, Lewis J: Continuum model of tendon pathology - Where are we now?. Int. J. Exp. Pathol. 2013; 94: 242–247. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDegen RM, Conti MS, Camp CL, et al.: Epidemiology and Disease Burden of Lateral Epicondylitis in the USA: Analysis of 85,318 Patients. HSS J. 2018; 14: 9–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbbott KV, Barton FB, Terhorst L, et al.: Retrospective studies: A fresh look. Am. J. Speech-Language Pathol. 2016; 25: 157–163. PubMed Abstract | Publisher Full Text\n\nDroppelmann G: Ultrasound findings in lateral elbow tendinopathy. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "128754",
"date": "21 Apr 2022",
"name": "Rodrigo Antonio Guzmán-Venegas",
"expertise": [
"Reviewer Expertise Biomechanics & Biomechanics of tissues"
],
"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 consists of a prospective design investigation where a secondary database was analyzed. The objective of the study was to identify the frequency and evaluate associations between standardized degenerative tendon findings with tendon tears in three size dimensions.\nThe selected methodology made it possible to adequately achieve the objective. The exposition of the method and its details makes the reproduction of the study feasible. Statistical methods seem adequate to me and the conclusions are based on the results obtained.\nThere are some small details that need to be corrected:\nIn the introduction, the authors refer to a process of neurovascular growth, perhaps they meant neovascular?\n\nIf possible to do so, terms must be translated into English in the following sentence: Comité de Ética Científico Adulto del Servicio Metropolitano Oriente de la ciudad de Santiago de Chile\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": "8146",
"date": "25 Apr 2022",
"name": "GUILLERMO DROPPELMANN",
"role": "Author Response",
"response": "Thank you very much for your comments. You must use the original or native name of the ethical committee. Neovascular growth or neovascular is the same. Thank you again for your effort and time. All the best."
}
]
},
{
"id": "148546",
"date": "07 Sep 2022",
"name": "Stefanos Karanasios",
"expertise": [
"Reviewer Expertise Musculoskeletal 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 current study as a retrospective analysis, offers several valuable results in the field of tendon radiological evaluation in patients with lateral elbow tendinopathy (LET). Methods are clearly described and results adequately presented. The authors discuss the interesting relationship between tendon degeneration, aging and the presence of tears which possibly adds a new perspective in the future research and clinical practice in the management of LET (tendinopathy continuum model). Authors adequately discuss the inherent limitations in a retrospective study i.e. lacking inter- intra tester reliability of ultrasonographers and correlation of patients' characteristics (pain, disability, chronicity etc.)\nSome points requiring further attention include:\n\"ultrasound (US) findings in the degenerative stage has been well documented21 and can be a useful tool to detect signs such as hypoechoic areas, neovascularization, calcifications, enthesopathy, and intrasubstance tears22 with better sensitivity and accuracy than magnetic resonance imaging (MRI).23,24\"\nContemporary evidence does not support this statement1.\n\nthe lack of evaluation of other ultrasound findings such as thickness, enthesopathy etc. could be discussed as a limitation\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-44
|
https://f1000research.com/articles/10-571/v1
|
15 Jul 21
|
{
"type": "Case Report",
"title": "Case Report: Priapism as the clinical presentation of chronic myeloid leukemia in accordance with reports created during last twenty years: a case report and literature review",
"authors": [
"Siprianus Ugroseno Yudho Bintoro",
"Pradana Zaky Romadhon",
"Satriyo Dwi Suryantoro",
"Rusdi Zakki Aminy",
"Choirina Windradi",
"Krisnina Nurul Widiyastuti",
"Siprianus Ugroseno Yudho Bintoro",
"Satriyo Dwi Suryantoro",
"Rusdi Zakki Aminy",
"Choirina Windradi",
"Krisnina Nurul Widiyastuti"
],
"abstract": "Priapism in chronic myeloid leukemia (CML) appears to be an infrequent manifestation as well as a crucial emergency. Here, we report an 18-year-old male presenting with a persistent erection of penis for 20 days. We evaluate and compare the reported cases during the past 20 years discussing the management of CML patients experiencing priapism. Cytoreductive therapy followed by leukapheresis, the administration of tyrosine kinase inhibitor, and intra-cavernosal blood aspiration may resolve the symptoms of priapism. Early intervention for cytoreduction and aspiration are the pivotal keys to successfully impeding the complications.",
"keywords": [
"priapism",
"chronic myeloid leukemia",
"cytoreduction",
"penile-aspiration",
"cancer"
],
"content": "Introduction\n\nPriapism is a urological emergency due to persistence of an erection lasting more than 4 hours, whether or not it is related to sexual influence.1 Priapism is a rare condition with an incidence of 1–5 cases per 100,000 people per year. Penile erection in priapism is regularly painless. There are two types of priapism, namely low-flow priapism and high-flow priapism. Low-flow priapism is provoked by a pathological condition of low venous blood flow causing stasis in the penile vessels. This condition is an emergency condition that can result in cell damage and fibrosis, so it often requires immediate therapy. Meanwhile, high-flow priapism is caused by increased blood flow to the sinusoid arteries without offsetting the flow to the veins. One of the causes of high-flow abnormalities is penile injury, while low-flow priapism is commonly caused by blood disorders such as sickle cell anemia and chronic myeloid leukemia (CML).2–4\n\nHematological abnormalities account for 20% of the incidence of priapism while leukemia cases account for 1–5% of priapism in men. The theory related to the occurrence of priapism is the dysregulation of nitric oxide (NO) in penile vascularization. This occurs due to changes in NO synthase enzyme activity which cause a decrease in NO production by the corpora cavernosa. This ischemic condition induces platelet aggregation and thrombus and tissue damage. The hematologic condition generates priapism with decreased NO which interferes with smooth muscle tone controlling penile tumescence. Hyperviscosity conditions due to leukocytosis and adenosine-opiorphins abnormalities is also involved in this condition.1\n\nCurrently, the approach to treating CML patients with priapism uses a modality of combination of systemic therapy (chemotherapy with hydroxyurea or tyrosine kinase inhibitors and leukapheresis) and local intracavernosal therapy. Some cases with late manifestations cause erectile dysfunction, gangrene and penile abscess.5 This case report and review aims to discuss the clinical characteristics and outcomes of CML patients who experience complications in the form of priapism.\n\n\nCase\n\nAn 18-year-old unmarried male student, presented at the ER complaining of persistent erection of the penis. The patient complained of persistent erected penis for 20 days before admission. There was no phase without an erection during those 20 days. Previously, there was no history of trauma to sexual stimulation, or consumption of certain drugs. The patient also complained of mild genital pain along with the onset of erection. There were no complaints about discoloration of the penis, becoming reddish, bluish, or pale. There was no sensation of numbness or numbness. The patient could urinate normally (see Figure 1).\n\nThe patient complained of alternating ringing in his right and left ears for 15 days accompanied by blurred vision. The patient also felt that his left side of stomach was slowly enlarging for 5 months. There was no bleeding and fever. Before coming to the ER, the patient was hospitalized at the regional hospital and received a blood transfusion and was diagnosed with a blood disorder.\n\nOn physical examination, there was no anemia and icterus. The spleen was palpable showing Schuffner 4 and Hackett 3. There was no enlargement of the lymph nodes. His laboratory findings were as follows: hemoglobin 10.4 g/dL; leucocytes 421,000 cells/mm3; platelets 407,000 cells/mm3; white blood cells differential 4.3/6.8/81.3/4.9/2.7; blood urea nitrogen 9 mg/dL; serum potassium 0.5 mg/dL, uric acid 6.5 mg/dL. Peripheral blood smear showed normochromic anemia, normocytic anisopoikilocytosis, leukocytosis (3% myeloblasts, 6% promyelocytes, 4% myelocytes, 2% metamyelocytes, 5% stab neutrophils, 63% segment neutrophils, 4% eosinophils, 6% basophils, 5% lymphocytes, 2% monocytes, atypical lymphocytes (+)) concluded as CML. The patient received hydroxyurea 2000 mg once daily at night, paracetamol 500 mg TID, and an urgent leukapheresis.\n\nThe patient underwent leukapheresis once per day (a total of three times since initial admission) with gradual improvement. Unfortunately, on the fourth day of treatment the patient felt a penis erection again with pain on a scale of 0–5. Local examination of the genitalia showed a maximal erected penis, with no discoloration indicative of hyperemia, cyanosis, or pallor. Blood gas analysis showed pH 6.95, pCO2 64 mmHg, HCO3 14 mEQ/L, Be -18 unit, so it was concluded that the patient had ischemic priapism. Therefore, the patient underwent urologic intervention by intracavernous aspiration producing 150 mL blood. Not long after the procedure, the patient's penis returned to an erection with bleeding from the puncture wound. It was decided that the patient undergo leukapheresis.\n\nOn the eighth day of treatment, the erection improved and the patient reported 1 on a pain scale. Quantitative BCR–ABL examination showed a positive result of 65% so that the administration of hydroxyurea was stopped and replaced by imatinib 400 mg once daily at night. On the twelfth day of treatment, the erection was completely resolved and the patient was successfully discharged from the hospital.\n\n\nDiscussion\n\nThis review presents data on patients who have priapism due to CML (see Table 1). The results of this review indicate that cases of priapism occurred in the age range 9–53 years and the average patient had episodes of priapism for 18 h to 7 days. Not all patients with priapism showed a typical clinical examination of CML in the form of splenomegaly but all of these patients had a hyperleukocytosis profile with a leukocyte count >200,000 cells/mm3. Some of them are equipped with data peripheral blood smear with excessive blast and identification of BCR–ABL gene. Only one case reported by Minckler et al. who reported a resolved erection with a cold shower but most cases needed medical and intervention therapy.6 Although the duration of symptoms varied, four cases reported complications following an episode of priapism. Patients with unfavorable outcomes received hydroxyurea, imatinib but failed to undergo urological emergency therapy in the form of failure of intra-cavernosa aspiration, surgical intervention and embolization.\n\nIn this case, the patient was 18 years old. Based on the literature, patients in every age group are at risk of developing priapism. However, there are two peaks in the age distribution that tend to experience this condition. The peak in pediatric age is between 5 and 10 years, especially in patients with sickle cell disease. While the second peak age is at sexually active phase between 20 and 50 years. Apart from being a condition of hypercoagulability, this condition may also be related to the abuse of erectile drugs.7\n\nHistory and physical examination are important when encountering cases of priapism. Laboratory tests are required to check for impaired coagulation and serum electrolytes. Some patients who are at high risk for priapism include users of intracorporal injection therapy for erectile dysfunction, coagulation disorders such as sickle cell disease and CML.2,4 In CML, hyperleukocytosis is thought to be the main cause of priapism. The main mechanism is the aggregation of leukemia cells in the corpora cavernosa and dorsal veins of the penis. Another thing that underlies the mechanical pressure in the abdominal veins due to the enlargement of the spleen.1\n\nThe data needed in the management of patients with this case are erection duration, pain scale, trauma, complete blood count, peripheral blood smear, penile blood gas analysis, bone marrow and polymerase chain reaction for BCR–ABL1 if necessary.1,2,4 In CML, the most common type of priapism is the ischemia one (veno-occlusive). Patients usually complain of rigid erection, which may be accompanied by pain characterized by reduced to no cavernous blood flow at all. Priapism that lasts for more than 4 hours indicates a compartment syndrome and may require emergency medical intervention.8\n\nThe American Urological Association recommends that systemic treatment of an underlying disorder, like CML, should not be the only one therapy for ischemic priapism. In this case, the patient has had an erectile episode since 20 days who most likely has had a compartment syndrome so that the intra-cavernous aspiration is required.1\n\nThe intra-cavernous aspiration procedure can be accomplished by giving the anesthetic injection first under the symphysis pubis. The penis is tied with a tourniquet followed by insertion of a 16–18-Gauge bivalve intravenous catheter into the corpus cavernosum. When the two corpora are fused, aspiration of 20–30 mL of blood can be undertaken. This procedure has 30% chances of success.8,9\n\nSystemic therapy is often used to reduce hyperviscosity is cytoreductive therapy such as high-dose hydroxycarbamide and tyrosine kinase inhibitors (TKI) with or without apheresis procedures. The dose of hydroxycarbamide that can be given is 2–6 grams divided into four doses per day that can reduce leukocytes by almost 60% in 24–48 h. In addition, TKI administration such as imatinib can be administered as soon as the diagnosis is confirmed. The recommended dose of imatinib is 400 mg once daily in the chronic phase, 600–800 mg once daily in the accelerated phase and 800 mg once daily in a blast crisis.9 In the case of CML in general, The IRIS study describes the effectiveness of imatinib therapy for complete hematological response (CHR), major cytogenetic response (McyR) and complete cytogenetic response (CcyR).4\n\nLeukapheresis can cause a rapid decrease in intravascular leukemia cells and improve tissue perfusion as well as complaints related to leukostasis (generally show pulmonary and central nervous system manifestations). One leukapheresis procedure can reduce the leukocyte count by 30–60%. Albeit leukapheresis can reduce leukocytes significantly and rapidly compared to chemotherapy, several studies have shown high all-cause mortality. According to 2016 apheresis guidelines, grade 1B of acute myeloid leukemia is recommended (strong recommendation, moderate quality evidence) with category 2 (second-line therapy), while for acute lymphoblastic leukemia cases grade 2C is recommended (weak recommendation, low quality evidence) with category 3 (the role of apheresis is not very clear). In this guideline, leukapheresis recommendations are not stated in cases of chronic myeloid leukemia.10 Several cases of priapism in this case review reported a successful combination of leukapheresis therapy with systemic oral CML therapy. Only one case by Rojas et al. underwent leukapheresis but failed to improve.\n\nThis case report and review presents a comparative presentation of patient characteristics, clinical characteristics of CML, laboratory profile, and therapeutic intervention for CML with priapism. Clinical presentation and early intervention are the keys to successful therapy in preventing complications. Systemic intervention combined with intraurethral therapy increase the success rate (see Figure 2).\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "References\n\nRodgers R, Latif Z, Copland M: How I manage priapism in chronic myeloid leukaemia patients. Br J Haematol. 2012; 158(2): 155–64. PubMed Abstract | Publisher Full Text\n\nShaeer OK, Shaeer KZ, AbdelRahman IF, et al.: Priapism as a result of chronic myeloid leukemia: case report, pathology, and review of the literature. J Sex Med. 2015; 12(3): 827–34. PubMed Abstract | Publisher Full Text\n\nPaladino N, Roldán D, Caram MS: [Priapism in pediatrics: initial presentation of chronic myeloid leukemia]. Arch Argent Pediatr. 2011; 109(5): e104–8. PubMed Abstract | Publisher Full Text\n\nGaye O, Thiam NM, Cassell A, et al.: Unusual Presentation of Priapism Associated with Acute and Chronic Myeloid Leukemia in Two Patients: Emergency Management. Case Rep Urol. 2020; 2020: 4982432. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSun HH, Zhang JH, DeWitt-Foy M, et al.: Urologic Management of Priapism Secondary to Chronic Myeloid Leukemia. Urology. 2019; 125: 24–8. PubMed Abstract | Publisher Full Text\n\nMinckler MR, Conser E, Figueroa JJ, et al.: The Semantics of Priapism and the First Sign of Chronic Myeloid Leukemia. Case Rep Emerg Med. 2017; 2017: 2656203. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNerli RB, Magdum PV, Hiremath SC, et al.: Priapism - A Rare Presentation in Chronic Myeloid Leukemia: Case Report. Urol Case Rep. 2016; 4: 8–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChang MW, Tang CC, Chang SS: Priapism--a rare presentation in chronic myeloid leukemia: case report and review of the literature. Chang Gung Med J. 2003; 26(4): 288–92. PubMed Abstract\n\nRajabto W, Djianzonie JAC, Pratisthita LB, et al.: Priapismus as Leukostasis Manifestation in Chronic Myeloid Leukemia. Acta Med Indones. 2020; 52(4): 420–2. PubMed Abstract\n\nSchwartz J, Padmanabhan A, Aqui N, et al.: Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016; 31(3): 149–62. PubMed Abstract | Publisher Full Text\n\nDhar J, Dhar J, Chhabra G, et al.: Priapism as a Debut Presentation of Chronic Myeloid Leukemia. J Coll Physicians Surg Pak. 2019; 29(1): 78–80. PubMed Abstract | Publisher Full Text\n\nBecerra-Pedraza LC, Jiménez-Martínez LE, Peña-Morfin I, et al.: Priapism as the initial sign in hematologic disease: Case report and literature review. Int J Surg Case Rep. 2018; 43: 13–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan A, Shafiq I, Shah MH, et al.: Chronic myeloid leukaemia presenting as priapism: A case report from Khyber Pakhtunkhwa. J Pak Med Assoc. 2018; 68(6): 942–4. PubMed Abstract\n\nQu M, Lu X, Wang L, et al.: Priapism secondary to chronic myeloid leukemia treated by a surgical cavernosa-corpus spongiosum shunt: Case report. Asian J Urol. 2019; 6(4): 373–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nClark AJ, Hsu P, Darves-Bornoz A, et al.: Case 3: Priapism in a 13-year-old Boy. Pediatr Rev. 2018; 39(12): 617–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumar P, Rahman K, Kumari S, et al.: Priapism as a rare presentation of chronic myeloid leukemia. J Cancer Res Ther. 2018; 14(6): 1442–3. PubMed Abstract | Publisher Full Text\n\nHuei TJ, Lip HT, Shamsuddin O: A rare presentation of chronic myeloid leukaemia with priapism treated with corporoglandular shunting. Med J Malaysia. 2018; 73(6): 420–2. PubMed Abstract\n\nErgenc H, Varım C, Karacaer C, et al.: Chronic myeloid leukemia presented with priapism: Effective management with prompt leukapheresis. Niger J Clin Pract. 2015; 18(6): 828–30. PubMed Abstract | Publisher Full Text\n\nVillegas Osorio JF, Corchuelo Maíllo C, Cuevas Palomino A, et al.: Ischaemic priapism as a presentation of chronic myeloid leukaemia. Arch Esp Urol. 2014; 67(8): 708–11. PubMed Abstract\n\nHazra SP, Priyadarshi V, Gogoi D, et al.: Pediatric priapism: a rare first manifestation of leukemia. APSP J Case Rep. 2013; 4(3): 39. PubMed Abstract | Free Full Text\n\nVeljković D, Kuzmanović M, Mićić D, et al.: Leukapheresis in management hyperleucocytosis induced complications in two pediatric patients with chronic myelogenous leukemia. Transfus Apher Sci. 2012; 46(3): 263–7. PubMed Abstract | Publisher Full Text\n\nGupta A, Seth T, Gupta A: Successful use of terbutaline in persistent priapism in a 12-year-old boy with chronic myeloid leukemia. Pediatr Hematol Oncol. 2009; 26(1): 70–3. PubMed Abstract | Publisher Full Text\n\nTazi I: Priapism as the first manifestation of chronic myeloid leukemia. Ann Saudi Med. 2009; 29(5): 412. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCastagnetti M, Sainati L, Giona F, et al.: Conservative management of priapism secondary to leukemia. Pediatr Blood Cancer. 2008; 51(3): 420–3. PubMed Abstract | Publisher Full Text\n\nYoshida K, Kinoshita H, Taniguti H, et al.: [Priapism complicated by chronic myelogenous leukemia (CML); a case report]. Hinyokika Kiyo. 2007; 53(5): 323–5. PubMed Abstract\n\nAllué López M, García de Jalón Martínez A, Pascual Regueiro D, et al.: [Priapism as an initial presentation of chronic myeloid leukaemia]. Actas Urol Esp. 2004; 28(5): 387–9. PubMed Abstract\n\nPonniah A, Brown CT, Taylor P: Priapism secondary to leukemia: effective management with prompt leukapheresis. Int J Urol. 2004; 11(9): 809–10. PubMed Abstract | Publisher Full Text\n\nDogra PN, Kumar P, Goel R, et al.: Long duration priapism in blast crisis of chronic myeloid leukemia. J Assoc Physicians India. 2004; 52: 170. PubMed Abstract\n\nCruz Guerra NA, Ramos LC, Linares Quevedo A, et al.: [Priapism secondary to chronic myeloid leukemia: value of initial treatment with cavernous lavage plus adjuvant methoxamine]. Arch Esp Urol. 2002; 55(3): 320–1. PubMed Abstract\n\nMurayama K, Shibuya A, Ishii S, et al.: [Embolization of the bilateral internal pudendal arteries for intractable priapism in a child with chronic myelogenous leukemia]. Rinsho Ketsueki. 2001; 42(11): 1117–1. PubMed Abstract\n\nRojas B, Cabrera ME, Kliwadenko W, et al.: [Priapism in a patient with chronic myeloid leukemia]. Revista medica de Chile. 1998; 126(8): 978–80."
}
|
[
{
"id": "89693",
"date": "18 Oct 2021",
"name": "Wulyo Rajabto",
"expertise": [
"Reviewer Expertise CML",
"lymphoma",
"anemia"
],
"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 case report emphasizes the importance of priapism as the rare clinical presentation of chronic myeloid leukemia so that as a clinician we should think if there is patient with priapism the secondary causal is chronic myeloid leukemia. The treatment of priapism consists of: 1) Local factor by urologist who performs intra cavernous aspiration 2) The systemic factor by hematologist who administers leucapheresis (mechanical and drug eg. Hydroxyurea) and TKIs such as Imatinib.\n\nI find the title of this manuscript indeed captivating. Besides describing the priapismus phenomenon in CML, the author also showed to us a comparison study among several previously published cases known worldwide, that I think it is a very interesting plus point.\nTitle: I believe it is very interesting, straightforwardly describes the case.\n\nIntroduction: I believe it contains concise reasoning why the author brought up this case, emphasizes the rare of similar cases, and interestingly presents one of CML emergencies.\n\nCase presentation: The author successfully managed to present the case elaborately along with valid data.\n\nDiscussion: The author describes the case comprehensively, referred to similar case studies before, from the clinical course to the outcome, as mention on table 1.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "100511",
"date": "02 Dec 2021",
"name": "Ritu Gupta",
"expertise": [
"Reviewer Expertise Hemato-Oncology",
"Genomics",
"Single-cell sequencing",
"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\nPriapism is an unusual complication of hematological malignancy with hyperleukocytosis and may be the presenting feature, especially in chronic leukemia as observed in this case.\n\nThe authors have described the clinical features, investigations, and management of the index case and reviewed the literature on the association of priapism with CML.\nI have a few comments/suggestions on this manuscript as detailed below:\nThe title is too long and can be abbreviated.\n\nReview of hematological malignancies presenting as priapism i.e. including CLL and Acute leukemia would benefit the readers in developing insight on the conditions in which priapism could be the presenting feature. A few references include the following: Johnson et al. (20201), Ali et al. (20212) and Gogia et al. (20123).\n\nThe meaning of some of the sentences is not clear in several places. The authors may focus on improving the language of the paper.\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? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "7535",
"date": "10 Dec 2021",
"name": "Pradana Zaky Romadhon",
"role": "Author Response",
"response": "Firstly, thank you for the detailed review and advice. We have simplified the title and removed unclear sentences then replaced them with more understandable ones."
},
{
"c_id": "7541",
"date": "10 Dec 2021",
"name": "Pradana Zaky Romadhon",
"role": "Author Response",
"response": "Dear Ritu Gupta, We already just submitted our new version of the manuscript. We also have included one of the references recommended by you in our discussion. Hope it will upgrade our manuscript quality. Thanks again."
}
]
}
] | 1
|
https://f1000research.com/articles/10-571
|
https://f1000research.com/articles/11-43/v1
|
13 Jan 22
|
{
"type": "Data Note",
"title": "COVID-19 risk perceptions and precautions among the elderly: A study of CALD adults in South Australia",
"authors": [
"Mohammad Hamiduzzaman",
"Noore Siddiquee",
"Helen McLaren",
"Noore Siddiquee",
"Helen McLaren"
],
"abstract": "Background: Coping with COVID-19 is a challenge for culturally and linguistically diverse (CALD) older adults. In Australia, little attention has been given to understanding associations between cultural contexts, health promotion, and socio-emotional and mental health challenges of older CALD adults during the COVID-19 pandemic. Therefore, we have collected data from older CALD adults to examine their COVID-19 risk perceptions and its association with their health precautions, behavioural dimensions and emergency preparation. Methods: A cross-sectional survey was conducted in South Australia. The CALD population aged 60 years and above were approached through 11 South Australian multicultural NGOs. Results: We provide the details of 155 older CALD South Australians’ demographics, risk perceptions, health precautions (problem-and-emotion-focused), behavioural dimensions and emergency preparation. The explanatory variables included demographic characteristics (age, gender, education and ethnicity); and risk perception (cognitive [likelihood of being affected] and affective dimension [fear and general concerns], and psychometric paradigm [severity, controllability, and personal impact]. The outcome measure variables were health precautions (problem-focused and emotion-focused), behavioral adaptions and emergency preparation. Conclusions: This dataset may help the researchers who investigate multicultural health or aged care in the pandemic and or who may have interest to link with other datasets and secondary use of this primary dataset in order to develop culturally tailored pandemic-related response plan. The data set is available from Harvard Dataverse.",
"keywords": [
"Culturally and linguistically diverse community",
"older adults",
"risk perceptions",
"health precautions",
"behavioural dimensions",
"emergency preparedness",
"South Australia"
],
"content": "Introduction\n\nThe COVID-19 pandemic is a global and national health emergency, affecting many Australians’ everyday lives and livelihood, including older adults.1 Older Australians aged 65 years and above account for 15% of the country’s total population, of which three in 10 were born overseas.2 The relationships between older Australian’s cultural backgrounds, health and quarantine protocols, as well as psychosocial and emotional wellbeing during the pandemic are unclear across the country, including in South Australia.\n\nThe pandemic has strained hospitals, public health and social services organizations in South Australia, as in other Australian jurisdictions, which raises concerns among older CALD adults about their health and emotional wellbeing. Older adults are more likely to be infected and die (i.e., about 78% of all COVID-19 patients who died were aged 65 years and above) than other age groups.3,4 The risks and fear are higher for older CALD adults because of common health concerns, such as a high rate of chronic conditions and comorbidities, avoiding medical appointments and acute care, chance of delaying care; risk of community transmission due to reluctance; and prevalence of depression and anxiety because of a separation from families and friends and a restriction of movement.5,6 They have been anticipated to experience changes in their wellbeing and quality of life during the pandemic, which have not been investigated. In addition, COVID-19 risk perceptions, psychological and emotional health-related worries and coping behaviours may vary in older CALD adults based on their age, gender, education, and ethnicity. Therefore, we have collected data from older CALD adults to examine their COVID-19 risk perceptions and their association with health precautions, behavioural adaptations and emergency preparation based on socio-demographic characteristics.\n\n\nMethods\n\nThis data note presents data from a cross-sectional study in South Australia from July 1 to December 31, 2020, involving basic demographic data collection and assessment of risk perceptions, health precautions, and emergency preparedness, to understand the relationships between risks perceptions of older CALD adults with their problem- and emotion-focused precautions, behavioural coping and emergency preparedness during the COVID-19 pandemic.\n\nData were collected from older CALD adults (≥60 years) through South Australian multicultural NGOs. The multicultural NGO selection process involved a primary search in the list of Australian accredited NGOs. Fifteen NGOs in South Australia were deemed appropriate for three reasons: they were accredited and active in the community; represented the majority of CALD communities; and had members of older CALD adults. The online survey (SurveyGizmo) was administered by sending an email invitation to 11 South Australian multicultural NGOs, who agreed to voluntarily distribute the participation information sheet and survey link to their older community members, resulted in 155 surveys completion. According to the Australia Bureau of Statistics, approximately 95,000 older CALD adults lived in South Australia in 2018. In our study, we aimed to approach 300 respondents based on the number of multicultural NGOs having agreed to support this study and computer illiteracy rates among the older CALD adults, which allowed for a dropout rate of less than 50%. We continued to collect data over a period of six months until we reached the saturation.\n\nThe outcome measures were health precautions (problem-focused and emotion-focused), behavioural dimensions and emergency preparation for coping with the COVID-19 crisis. The scale included nine items relating to problem-focused precautions and 10 items assessing emotional precautions. Seven behavioural dimensions items and five related to emergency preparedness during the pandemic were considered as outcome measures. The demographic characteristics and risk perception data were collected as explanatory variables. Participant demographics were categorized into: age (60-69 years, 70-79 years, and 80 years and above); gender (male and female); education (no formal education, primary school, high school, Bachelors, and Masters and above); and ethnicity (country of birth; classified as Asian, African, and non-English speaking self-nominated CALD European). We used the modified version (i.e., a 15-indicator risk perception scale) of Gerhold’s (2020) COVID-19 risk perception measure, which was developed based on Slovic’s (1987) psychometric concepts— a) cognitive (i.e., likelihood of being affected) and affective dimension (i.e., fear and general concerns), and b) psychometric paradigm (i.e., severity, controllability, and personal impact).\n\nDescriptive analysis was conducted for demographics, indicators of risk perceptions, as well as the problem- and emotion-focused precautions, behavioural dimensions and emergency preparation. To examine the associations between the explanatory variables and the outcome measures, several multiple linear regression models were fitted. Multicollinearity was checked in the regression analyses by examining the tolerance values. The entire analysis was performed with STATA/MP version 13.0 (StataCorp, LP, College Station, Texas, USA).\n\nThis dataset has some limitations. It is a cross-sectional study, therefore, causal inferences about the relationship between socio-demographic characteristics and risk perceptions, health precautions, behavioural adaptations, and emergency preparation could not be measured. Our study sample was not representative of all CALD communities in South Australia and the findings may not be generalised to other CALD populations, either in Australia or overseas. Also, we relied on an English-language online questionnaire for data collection, which had an influence on participation rates.\n\nHowever, we employed several strategies to ensure validity and reliability of the dataset. In measuring the risk perceptions, we used Gerhold’s (2020) COVID-19 risk perception scale, developed based on Slovic’s (1987) psychometric concepts: a) cognitive (i.e., likelihood of being affected) and affective dimension (i.e., fear and general concerns); and b) psychometric paradigm (i.e., severity, controllability, and personal impact). The 19 indicators of health precautions, seven items of behavioural adaptations, and five items of emergency preparation scales were drawn from Folkman and Lazarus’s (1988) problem- and emotion-focused coping, which have been used by scholars to measure similar outcome variables in other countries. Reliability in data items was separately checked using Cronbach’s α, a commonly cited test to check internal consistency of a scale.7 Internal consistencies were: three items of becoming infected (α = 0.9073); two-items of fear (α = 0.8863); nine items of problem-focused health precautions (α = 0.7964); 10 items of emotion-induced health precautions (α = 0.7050); seven items of behavioural adaptations (α = 0.7927); and five items emergency preparations was 0.83 (Cronbach’s α = 0.8292).\n\nIn order to control bias, the SurveyGizmo software was used for data collection. The participants were approached and recruited by the NGOs, and they were given the opportunity to share their email address to receive a copy of study results and review.\n\nThe study received ethical approval from the Flinders University Human Research Ethics Committee, Australia (Approval number: HEL2215). A group of 11 South Australian multicultural NGOs provided written informed consent in supporting the researchers for participant approach and recruitment. Informed consent for the participation was implied, as the completion of online survey was considered written informed consent. The data collected from participants were only used for this research.\n\n\nData availability\n\nHarvard Dataverse: COVID-19 Risk Perceptions and Precautions among the Elderly: A Study of CALD Adults in South Australia, https://doi.org/10.7910/DVN/OUGSUC.8\n\nThis project contains the following underlying data:\n\n• COVID-19 Latest Dataset.SPSS. (Contains data in SPSS of the older CALD adults’ socio-demographic variable, risk perceptions, problem and emotion-focused precautions, behavioral dimensions and emergency preparation).",
"appendix": "Acknowledgements\n\nWe are thankful to the participants who provided time and shared their experiences about the COVID-19. We acknowledge the contribution of CALD community NGOs which helped the researchers in distributing the survey questionnaire and encouraging people to participate. We thank the project’s Research Assistant for her valuable support to the Multicultural NGOs in participants’ recruitment and in data collection.\n\n\nReferences\n\nRahman MM, Bhattacharjee B, Farhana Z, et al.: Age-related Risk Factors and Severity of SARS-CoV-2 Infection: a systematic review and meta-analysis: symptoms and comorbidity estimation, and their association with age. J. Prev. Med. Hyg. 2021; 62: 1–11.\n\nPham TT, Berecki-Gisolf J, Clapperton A, et al.: Definitions of Culturally and Linguistically Diverse (CALD): A Literature Review of Epidemiological Research in Australia. Int. J. Environ. Res. Public Health. 2021; 18(2): 737. PubMed Abstract | Publisher Full Text\n\nMoss R, Wood J, Brown D, et al.: Modelling the impact of COVID-19 in Australia to inform transmission reducing measures and health system preparedness. medRxiv. 2020.\n\nPayne JL, Morgan A, Piquero AR: COVID-19 and social distancing measures in Queensland, Australia, are associated with short-term decreases in recorded violent crime. J. Exp. Criminol. 2020; 29: 1–25.\n\nBenham JL, Lang R, Kovacs BK, et al.: Attitudes, current behaviours and barriers to public health measures that reduce COVID-19 transmission: A qualitative study to inform public health messaging. PLoS One. 2021; 16(2): e0246941. PubMed Abstract | Publisher Full Text\n\nFaasse K, Newby J: Public Perception of COVID-19 in Australia: perceived risks, knowledge, health protective behaviours and vaccine interests. Front. Psychol. 2020; 11. PubMed Abstract | Publisher Full Text\n\nHeo M, Kim N, Faith MS: Statistical power as a function of Cronbach alpha of instrument questionnaire items. BMC Med. Res. Methodol. 2015; 15(1): 1–9.\n\nHamiduzzaman M, Siddiquee N, McLaren H: COVID-19 Risk Perceptions and Precautions among the Elderly: A Study of CALD Adults in South Australia. Harvard Dataverse. 2021; V1. Publisher Full Text"
}
|
[
{
"id": "119644",
"date": "19 Jan 2022",
"name": "Dr. Yang Wang",
"expertise": [
"Reviewer Expertise Science of science and research method for primary care 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\nThanks for inviting me to peer review this paper.\nThis paper reported a survey to older CALD adults about risk perceptions and precautions in South Australia. However, I still cannot understand its aim very well, because there is a contradiction between its title, research question and results: is the aim of this paper to report the finding of a cross-sectional survey or just provide a dataset? If its aim is to provide a dataset, it is proper to be published after revision, because it can help more people to understand the situation of older CALD adults under the threat of covid-19. If its aim is to report the finding of a cross-sectional study, the authors may need to provide more information in the manuscript according to STROBE checklist.\nSpecifically, I suggest the authors should provide more information to readers more clearly:\n(1) How many jurisdictions are there in Australia? Is the situation of older CALD adults between South Australia and other jurisdictions similar?\n(2) What are the inclusion and exclusion criteria for select the participants (older CALD adults)?\n(3) References 5 and 6 do not provide supportive information about the higher risk of older CALD adults. Please check it.\n(4) For a cross-sectional survey, saturation is not an applicable concept (it is often used in qualitative research). What we need to know is the instrument, survey approach, sample size and sampling method, because they can decide if we can obtain reliable information representing the real situation of the target population.\n(5) What are “computer illiteracy rates”? I can't understand its relationship with older CALD adults.\n(6) The information about the verification of Gerhold’s COVID-19 risk perception scale, Folkman and Lazarus’s problem and emotion-focused coping may need to be moved to the 'Source of data' section, because it is the verification of the instrument. The validation of the dataset may be different to the validation of the instrument. Please read: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395976/\n(7) If the aim of this paper is only to provide a dataset, it seems unnecessary to use multiple linear regression to calculate the causal relationship between factors.\nBest wishes\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "123067",
"date": "07 Mar 2022",
"name": "Binahayati Rusyidi",
"expertise": [
"Reviewer Expertise qualitative research",
"social welfare"
],
"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 title of this study is interesting. The research is also important because the issues are understudied.\nHowever, in my opinion, there is an inconsistency between the purpose of the study and the results. Based on the research questions, I expected to get comprehensive descriptions and analysis about factors associated with Covid-19 risk perceptions among CALD adults. The manuscript, unfortunately, provides little information about the results and discussion of the findings.\nIf the study is to report the results from a study, I suggest the authors do some revisions that follow the standard for publishing an empirical study.\nIn addition, some additional revision or clarification could be incorporated including:\na. Strengthening the position of the study within the existing knowledge about the issue. While the authors have stated that the topic covered by their research is rarely studied in Australia, it is important to see what is available globally.\nb. It will be better if the authors can provide a socio-demographic description of 95,000 CALD adults in South Australia in 2018. This information can be helpful when doing the analysis of the study, for example to check whether the participants of the study proportionately or disproportionately represent the CALD adults general population.\nc. It might be more helpful for the readers if the authors can provide examples of items assessed by the instruments used to measure dependent and independent variables.\nd. The information for validity and reliability checking of Covid-19 risk perception measure can be moved to source of data sub-section. There is limited information about instruments used to measure outcome variables, so I assume they are self-developed instruments? Information about internal consistency tests for these instruments can be provided as well.\ne. I am wondering why the length of stay in Australia and the nature of living arrangement of participants are not assessed as demographic variables in the study because I think they are possibly associated with the outcome variables. Some explanation about this?\nf. The term \"saturation\" stated in the data collection process is usually used in qualitative research, not in quantitative study.\ng. I am not clear with the term computer illiteracy rates stated in the manuscript. Did the researchers try to explain that they anticipated high rates of CALD adults who are computer illiterate?\nh. The researchers mentioned multicollinearity checking but there was no information whether multicollinearity was an issue or not.\n\nIs the rationale for creating the dataset(s) clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "125331",
"date": "18 Mar 2022",
"name": "Sharif Rasel",
"expertise": [
"Reviewer Expertise business research involving quantitative analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks for the opportunity to review this article. The authors have followed a rigorous statistical method to conduct the data analysis. However, the authors may consider to report the test of common method variance and non-response bias. Further, they may also include factor loadings of the items. In my view, the article may be considered for publication.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-43
|
https://f1000research.com/articles/11-42/v1
|
13 Jan 22
|
{
"type": "Study Protocol",
"title": "Causes and consequences of psychological stress in the working life and emergency services of veterinary professionals in the Federal Republic of Germany: A protocol for a nationwide cross-sectional study",
"authors": [
"Irina Böckelmann",
"Robert Pohl",
"Sabine Darius",
"Beatrice Thielmann",
"Irina Böckelmann",
"Sabine Darius",
"Beatrice Thielmann"
],
"abstract": "Background: Veterinarians are exposed to high workloads. International studies show they have an above-average risk of suicide and burnout. Hardly any studies dealing with causes and consequences of workload and emergency services are available in Germany. Methods: The aim of the observational cross-sectional study presented here is to assess their workloads and working conditions (Slesina questionnaire), health situation and well-being (KÖPS questionnaire - physical, psychological and social symptoms; Maslach Burnout Inventory MBI-GS; WHO-5 well-being index), as well as occupational psychological aspects (irritation scales; overcommitment; questionnaire on work-related behavior and experience patterns AVEM) which will be recorded and analyzed according to general sociodemographic and occupational data (sector-, gender, assignment- and country-specific). In addition, the heart rate variability of some members of the veterinary profession will be analyzed using 24 hour electrocardiogram recordings, which together with the subjective insights into the stress situation from the questionnaires, will allow objective psychophysiological stress analyses. Conclusions: The results of the study will provide further empirical insights into the workloads and stresses faced by the veterinary profession in Germany, based on which important insights into this professional group’s mental health can be identified. In this way, it should be possible to identify (mis)stress-triggering factors in the target groups, derive target group-specific recommendations for health-promoting work design, and identify approaches to veterinary studies and career selection.",
"keywords": [
"study protocol",
"veterinarians",
"workloads",
"psychological stress",
"heart rate variability"
],
"content": "Introduction\n\nVeterinarians’ stressful work situation, the permanently high demands made on the services provided and on themselves, the high level of responsibility and the economic pressure in veterinary practice, do not entirely correspond to society’s view of this profession. This also applies to the expectations that people have of veterinary medicine when choosing a profession.\n\nThe number of veterinarians practicing veterinary medicine in Germany was 32,582 as of December 31, 2020, of whom 22,121 (67.9%) were female.1 765 of the 881 veterinary medicine students who successfully passed the state examination in 2020, were female (86.8%) (plus 41 foreign students, of whom 33 were female).1 Therefore, for the purposes of health research, it should be noted that the gender ratio in veterinary medicine is much skewed.\n\nNumerous studies, mainly international, have specifically confirmed psychological distress and an increased prevalence of depressiveness and suicidality or suicide risk among practicing veterinarians.2–4 A review showed that those most at risk for exhibiting suicidal ideation, mental health problems, and dissatisfaction with the profession are predominantly young and female veterinarians.5 The relationship between poor working conditions and negative long-term stress outcomes is also presented in the literature.5 For example, in her survey, Geuenich6 also reports that psychosomatic complaints occur in 38% of the surveyed veterinarians who work more than 45 hours per week. Stress-related alcohol and medication consumption could also be identified and are possible adverse health reactions to job-related stress. A recently conducted online survey on veterinarians’ suicide risk confirmed an increased prevalence of suicide compared with the general population and examined veterinary professionals’ work stresses, controlling for age and gender.4 Early career veterinarians are under permanently high pressure to perform, both in the context of practice management and in relation to the animal’s owner. Permanent stress increases the risk of accidents. Studies in veterinary educational institutions also indicate that students have high levels of stress in several areas of life.7\n\nThe Federal Association of Veterinary Medicine Germany (BVVD 2020) calls for mental health issues to no longer be accepted as a social taboo in veterinary medicine studies and urges the creation of a common awareness of this sensitive topic, and exchange and cohesion among members of the profession. A subjective perception of one's own efficiency as well as one’s competence for self-fulfilment and to deal with stressful situations are not only important during one’s veterinary studies but also later when practicing in the profession. In terms of preventive medicine, it makes sense to learn such competencies early in veterinary school and to adapt and optimize them throughout one's professional life. A study in veterinary practice showed that there is a relationship between well-developed communication skills and job satisfaction while studying, retention in the profession as a veterinarian, client satisfaction, reduced litigation, and veterinarians’ financial compensation.8\n\nThe results of the empirical study on stress and substance use (tobacco, alcohol, medication) carried out as part of a joint effort by the University of Applied Sciences and the Professional Association for Health Services and Welfare Care (BGW),9 show that on average, veterinarians are generally not affected much by psychosocial stress and demoralization. However, these results suggest that stress is mainly triggered by long working hours and dealing with difficult customers. The alcohol consumption in the survey was higher than in the general population; in particular, the alcohol consumption by women was more often risky or dangerous. Severe psychosocial stress and emotional tension are often associated with increased alcohol consumption and substance abuse in studies. In an online survey conducted by the German Veterinary Journal and the German Medical Association in November 2010, nearly 6% of the 2,642 veterinarians surveyed reported significant to heavy stress-related alcohol and/or medication use.10 A study from England showed that although veterinarians drink more frequently than the general population, they consume less on an ordinary day. The prevalence of daily and weekly binge drinking is similar to that of the general population.11\n\nPsychobiological mechanisms play a role in the pathogenesis of many diseases associated with work-related stress. Different psycho-neurophysiological mediation pathways, such as the autonomic nervous system (ANS), the endocrine system and the immunological system, are responsible for maintaining internal homeostasis in stressful situations. A disbalance between sympathetic and parasympathetic regulation can be objectified using heart rate variability (HRV) as a parameter of autonomic heart function and general activation in one of the organism’s complex autonomic regulatory systems. Lower HRV is associated with deviant regulatory mechanisms and impaired adaptive cardiovascular system capacity (CVS).\n\nThe need for further surveys and analyses of workloads and stresses among physicians working in veterinary medicine is the subject of the nationwide study, Causes and consequences of psychological stress in the working life and emergency services of veterinary professionals in the Federal Republic of Germany. This will take into account factors that have never, or hardly ever, been considered so far, including emergency service participation and differences between rural and urban veterinarians. Furthermore, additional physiological stress parameters could provide information about stressful work situations for veterinarians through HRV analyses.\n\nFollowing an introductory comparative analysis of the work situation, the aim of the study is to analyze the physical and psychological stresses and strains affecting the professional group of veterinarians in different areas (small animals, horses, livestock, laboratory area and authorities). This will take into account possible influencing factors, such as age, gender, educational and professional biography, working environment (big city, small town, rural area) and the federal state, as well as examining the influence of these factors on the employees’ health.\n\nFurther aims are to analyze the causal relationship between workload and health consequences, to identify the role of organizational factors in emergency services, and to derive target group-specific recommendations for action on health-promoting work design.\n\nThis results in the following central questions guiding the research:\n\n- To what extent do stresses, strains and resources differ among veterinarians in different fields?\n\n- What are the influencing factors and predictors of occupational stress and strain?\n\n- What influence do work-related behavior, experience patterns and the handling of stressful situations have on veterinary professionals’ mental health?\n\n- To what extent do stressful situations during emergency service differ between veterinarians in different areas? Are there differences between an emergency service in rural areas and in the city?\n\n- To what extent do the subjective assessment and objective determination of the stress experienced in stressful situations correspond?\n\n- Which target group (occupational group areas, e.g., small animals, horses, livestock, laboratory area and authorities; areas of application, e.g., big city, small town, rural area; age and gender) specific recommendations for action for health-promoting work design can be derived from this?\n\n- How should the data from Germany be assessed in an international comparison?\n\n\nMethods\n\nThe protocol was developed with close reference to the STROBE checklist.\n\nThe study consists of an observational cross-sectional design and is divided into 2 parts (Part A and Part B), each with subjective and objective data collection instruments. Part A of the study consists of an online survey (July 01, 2021 to January 31, 2022). The longer survey period makes it possible for veterinarians who have been ill for a longer period of time to participate in the study. In addition, the nationwide survey should avoid a selection bias. The online survey reduces responses in terms of social desirability, as these can only be evaluated anonymously. Answers to specific questions which were developed for this study, about socio-demographic data, job characteristics and organizational conditions are recorded in such a way that comparisons between various specific target group are possible. This means that account must be taken in all areas of veterinary practice (small animals, horses, livestock, laboratory area and authorities) and especially in emergency services, we must take into account aspects such as area (big city, small town, rural area), gender, assignment, country specifics, contexts of professional development, and work organization.\n\nFurthermore, selected standardized instruments for recording stress and strain (as well as other relevant constructs such as well-being, etc.) will be included. In addition, standardized questionnaires about handling stressful situations and willingness to expend energy will also be used. All questionnaires used are standardized valid procedures. The full list of questionnaires used for this study are as follows: questionnaire according to Slesina,12 KÖPS Questionnaire,13 MBI-GS,14 WHO-5,15 IS,16 OC,17 AVEM,18 DSI19 and the MIGA-Heart Questionnaire.20 Some of the questionnaires (KÖPS, AVEM, DSI) can be evaluated with the Vienna Test System (version 8, Company Schufried, Mödling, Austria), however the software is not necessary.\n\nPart A (online survey; software SoSci program version 3.2.03-i)\n\n1. Socio-demographic data, occupational history, working conditions\n\na. General information and socio-demographic data (e.g., age, gender, etc.)\n\nb. Information about the respondent’s professional situation\n\nc. Information about workload and working conditions (questionnaire according to Slesina).12 Main variables: Subjective physical workloads (for example: noise, posture, odors, overtime)\n\n2. Questions about the respondent’s health and well-being.\n\na. Information about the respondent’s health situation: physical, psychological and social symptoms (KÖPS).13 Main variables: mental impairments, physical impairments, and social-communicative impairments.\n\nb. Maslach-Burnout-Inventar (MBI-GS).14 Main variables: emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA). Burnout risk according to Kalimo et al.21\n\nc. WHO Well-being (WHO-5).15 Main variables: ‘I have felt cheerful and in good spirits’, ‘I have felt calm and relaxed’, ‘I have felt active and vigorous’, ‘I woke up feeling fresh and rested’ and ‘My daily life has been filled with things that interest me’\n\n3. Occupational medicine-psychological section\n\na. Irritation scales (IS).16 Main variables: mental fatigue and mental illness\n\nb. Overcommitment (OC).17 Main variables: Effort and reward\n\nc. Questionnaire on work-related behavior and experience patterns (AVEM).18 Main variables: Pattern G (Healt), Pattern S (Unambitious), Pattern A (Overexertion) and Pattern B (Burnout)\n\nPart B consists of psychophysiological examinations (01 October 2021 to 31 March, 2022). The subjects’ 24-hr Electrocardiogram (ECG) recordings (medilog® AR12 PLUS, Fa. SCHILLER, Baar, Switzerland); provide a basis for the HRV analysis. The RR or Normal-to-Normal (NN) time series are processed with the software medilog® DARWIN2 Enterprise Version 2.9.2 for the total recording time (for example with 24 hours recordings), and an artifact correction is performed. An alternative software that can provide an equivalent function is the custo flash 500/510/510V (custo med GmbH, Ottobrun, Germany). HRV parameters are calculated from these data using Kubios HRV 3.3.1 software (University of Eastern Finland, Kuopio, Finland). An alternative that can provide an equivalent function is the HRV-Scanner Version 3.0 (BioSign GmbH, Ottenhofen, Germany). HRV analyses are performed according to the guideline for the application of heart rate and heart rate variability in occupational medicine and occupational science22 and with the same recording period and recording lengths to avoid bias in the analyses. HRV analysis is performed in the time and frequency domain and with nonlinear methods. Table 1 provides an explanation of the HRV parameters used.22,23\n\nSubjects who participate in the HRV analysis will complete the standardized MIGA-Heart questionnaire20 to assess the factors which influence HRV, in addition to the Differential Stress Inventory (DSI) questionnaire,19 which is also standardized, to assess and classify the individual's experience of stress. Both questionnaires are completed immediately before the HRV recording period. The goal is to obtain a 24-hr emergency/standby ECG recording and a 24-hr non-emergency/standby recording for each subject. In addition, the subjects will keep a log to document their daily activities (for example, sleep times).\n\nPart B\n\n1. Psychophysiological examinations\n\na. Per subject, two long-term (24-hr) ECG with subsequent analysis of HRV.\n\nb. MIGA-Heart questionnaire to assess the factors influencing HRV.20 Main variables: Socio-demographics and factors influencing HRV (for example: Taking medication, physical activity, body mass index (BMI)).\n\nc. DSI.19 Main variables: Type I (normal type), Type II (overstressed), type III (stress resistant), type IV (low stress/high coping) and type V (high stress/high coping).\n\nd. Protocol of the activity during the 24-hr\n\nThe study population consists of practicing veterinarians in Germany. For organizational reasons, the planned HRV analyses are limited to the region in and around Magdeburg in the federal state of Saxony-Anhalt, Germany.\n\nThe recruitment is done by advertising the study through the German Veterinary Association, the state veterinary associations and through additional information in the journal Deutsches Tierärzteblatt (issue 09/2021), as well as via social media (Facebook, Instagram). In addition to a link to the study, a QR code has also been generated so that subjects willing to participate can access the online survey directly.\n\nThe veterinary community in Magdeburg (capital of Saxony-Anhalt) and the surrounding area will be contacted directly regarding the planned psychophysiological examinations (HRV analysis), using the veterinary practices’ e-mail.\n\nThe study will include veterinarians who work in a wide variety of fields in the Federal Republic of Germany (small animals, horses, farm animals, laboratory field and public authority) and who have been working in their fields for at least one year.\n\nThe inclusion criteria for subjects for part B (the HRV analyses using ECG recordings) are based on the S2k guidelines for the use of heart rate and heart rate variability in occupational medicine and occupational science.20\n\nIn general, trainee veterinarians (veterinary students) and veterinarians with less than one year of active professional experience will not be included in the study.\n\nSubjects will be excluded from Part B of the study (ECG recording) for the following reasons: Cardiac arrhythmias, cardiac disease, diabetes mellitus, untreated thyroid disease and treated thyroid disease with thyroid blood levels outside the normal range and sustained use of medications affecting cardiac rhythm (e.g., beta-blockers, alpha-receptor blockers, calcium antagonists, ACE inhibitors). A further exclusion criterion for the HRV analysis is a number of (ventricular and supraventricular) extrasystoles greater than 1% of all cardiac actions.22,24 Therefore, subjects who do not have any known cardiac arrhythmias but have more than 1% of extrasystoles in the ECG, will also be excluded from the statistical analysis of HRV data.\n\nSample size was calculated using the Hemmerich-StatistikGuru (version 1.96). An open-access alternative that can provide an equivalent function is the G*Power program (version 3.1.9.7, Heinrich- Heine-University Düsseldorf, Düsseldorf, Germany).\n\nPrevious studies of the professional group were used for the case number analysis.4,9 The following parameters were considered in the case number design: Test = single-factor analysis of variance (ANOVA); Number of groups = 4 (Field of activity) or 8 (Field of activity and sex); Type of power analysis = A priori; Tails = Two; Effect size ŋ2 = 0.06 (medium effect); Alpha level α err prob = 0.05; Statistical power (1-β err prob = 0.8). The number of subjects needed would be 44 (Field of activity) or 29 (Field of activity and sex) per group (A total of 176 and 232, respectively). These findings, as well as experience of the frequency with which the exclusion criteria for HRV analysis occurred, were used for our own sample size analysis. The quantitative survey was conducted in two parts: Part A) the online survey of the total sample (minimum n = 232) and Part B) additional determination of HRV from the 24-hr ECG recordings on a smaller sample from Magdeburg and the surrounding area (minimum n = 20).\n\nThe data collected from the participating subjects are anonymized, the assignment of the data from part A to the data of part B is done according to an entered 6-digit code, which is only known to the participant. The evaluation of the questionnaires and the ECG/HRV data is carried out by scientific staff of the Occupational Medicine Department in compliance with the obligation to maintain confidentiality as well as the General Data Protection Regulation and the Federal Data Protection Act.\n\nThe first main analyses will be descriptive with missing values being excluded. We will use the Wilcoxon test (for continuous parameters) to make comparisons between groups.\n\nThe comparisons will be made within occupational groups of veterinarians working in different fields (small animals, horses, farm animals, laboratory field and authorities), and will take into account the possible influencing factors such as age, gender, own educational and occupational biography, working environment (big city, small city, rural area) and German state, and their influences on the employees’ health.\n\nThe comparison of the mean values is carried out using either a t-test for normally distributed interval-scaled variables (in the case of two independent groups) or covariance analyses ANOVA (in the case of more than two independent groups). The non-normally distributed or ordinal scaled variables are calculated using the Mann-Whitney test and Kruskal-Wallis test, respectively.\n\nMultiple testing procedures are used for the statistical analyses of the effect relationship of workload and health consequences in order to elaborate the role of organizational factors in emergency services and so that target group-specific recommendations can be derived for taking action on health-promoting work design.\n\nThe significance level α is set at 5%. Corrections are made in each case using Bonferroni-Holm correction, to avoid α-error accumulation in the HRV parameters.\n\nStatistical analysis of the data is performed using the SPSS program version 26 (IBM, Armonk, NY, USA). An open-access alternative that can provide an equivalent function is the R stats package (R Project for Statistical Computing). The evaluation of the KOEPS, AVEM and DSI questionnaires is computer-assisted, using the Vienna Test System (version 8, Company Schufried, Mödling, Austria). Alternatively, the questionnaires can be evaluated manually.\n\nThe study (parts A and B) has been approved by the Otto-von-Guericke University Magdeburg ethics committee (No. 91/21). All those participating in parts A and B of the study do so voluntarily. For Part A (online survey), a link is available to the subjects, which is filled out and evaluated anonymously. This is done without consent. The subjects provide written informed consent for participation in Part B after they have been informed in detail about the procedure, risks and objectives of the ECG recording. The subjects will be given an information sheet and an informed consent form for this purpose. The subjects give their consent to participate in the form of a signature on the consent form provided for this purpose. In both parts of the study (parts A and B), the subjects are informed that their data will be analyzed anonymously and used for publications without drawing any conclusions about their personal details. If requested, the subjects receive the evaluation of their ECG results.\n\nThe results of the study will be published in international occupational science and occupational medicine journals (also open access/open source) and in practice-oriented journals, such as the Deutschen Tierärzteblatt, as well as other publication organs. In addition, the findings of this study may be shared in the context of relevant training courses (veterinary medicine at various locations, human medicine at the Otto von Guericke University Magdeburg, health promotion/health management and health promoting organizational development at the University of Applied Sciences Magdeburg/Stendal). The study can be viewed in the German Register of Clinical Studies under the registration number DRKS00026106.\n\n\nStudy status\n\nThe online survey has been active since 15/06/2021. At the time of writing, n = 642 subjects have participated in the survey (as of 13/09/2021). The recruitment of subjects for the 24-hr ECG recordings needed for part B will begin in October 2021. The expected end date of the study is 30/06/2023.\n\n\nConclusions\n\nThe study reflects a nationwide target group specific survey on stress and strain among veterinarians in Germany. Due to its use of seven validated questionnaires (plus an eighth, the DSI, for the 24-hr ECG recordings), the study has a broad design to better understand the causes and consequences of the work situation in the veterinary profession. This is an addition to the limited number of studies in Germany related to the mental health of veterinarians and may provide important insights into relevant work demands, work resources and personal resources, as well as the risk of burnout among veterinarians. This target group comparison allows new insights to be gained in the field of stress/strain research in this professional group. Socio-demographic developments, such as age structure, marital status, professional situation, self-employment, differences in emergency service between urban and rural areas, and their effects, for example, on stress situations in emergency service and the health of the increasingly \"female\" veterinary profession, have not yet been adequately researched. Therefore, they are also collected in this study and taken into account in the statistical analyses. In her research, Kersebohm25 raises the proposition that demographic changes are also accompanied by changing demands on working conditions. Future research could pursue this point, also in connection with the prevention of the negative health effects of mental stress. Many factors may play a role, such as changes in gender redistribution or demographic shifts in the age structure (employment into old age in the veterinary profession: according to the 2019 statistics of the state/veterinary chambers,26 the number of veterinarians working in the 60-69 age group was 6,290, in the 70-79 age group 3,488, in the 80-90 age group 2,020, and 311 in the over 89 age group) and/or different stress levels in the different veterinary fields.\n\nBy including the HRV analysis, a measurement method recognized within occupational medicine and science, the study has also expanded to include objective physiological stress parameters. This allows comparative stress analyses to be made between emergency services and a baseline of “normal” working days.\n\nThe everyday stress situation with long working days could be exacerbated by subsequent emergency service, leading to low job satisfaction and health impairments. (Incorrect) exposure to work stressors can be reduced through work-related and individual resources, social support, and using health-promoting work and behavioral practices. Organizational, social, and personal resources are considered compensatory and protective components. A strategy to prevent the long-term consequences of psychological stress can only be achieved by considering health risks and resources together.27\n\nThe risk assessment of mental stress, which is obligatory under occupational health and safety laws, is essential for detecting veterinarians’ mental problems in the workplace. Prevention of mental illness and health promotion can generally only be done well if the triggering demands and mental stress are counteracted. In addition, negative short-term consequences of stress should be recognized as early as possible so that the respective person can be helped at an early stage, thus directly preventing negative long-term consequences of stress which could necessitate early retirement.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Acknowledgements\n\nWe would like to thank the State Veterinary Chamber of Saxony-Anhalt for their support in conducting the study.\n\n\nReferences\n\nTierärztestatistik: Zusammenstellung der Daten aus den Landes-/Tierärztekammern. Deutsches Tierärzteblatt. 2021; 5(69): 558–568.\n\nGardner DH, Hini D: Work-related stress in the veterinary profession in New Zealand. N. Z. Vet. J. 2006; 54(3): 119–124. PubMed Abstract | Publisher Full Text\n\nBartram DJ, Baldwin DS: Veterinary surgeons and suicide: a structured review of possible influences on increased risk. Vet. Rec. 2010; 166(13): 388–397. PubMed Abstract | Publisher Full Text\n\nSchwerdtfeger K, Glaesmer H, Bahramsoltani M: Tierärztinnen und Tierärzte sind häufiger suizidgefährdet als andere Berufsgruppen. Deutsches Tierärzteblatt. 2020; 68(7): 848–849.\n\nPlatt B, Hawton K, Simkin S, et al.: Suicidal behaviour and psychosocial problems in veterinary surgeons: a systematic review. Soc. Psychiatry Psychiatr. Epidemiol. 2012; 47(2): 223–240. PubMed Abstract | Publisher Full Text\n\nGeuenich K: Stress im Tierarztberuf als Gesundheitsrisiko: Ergebnis der Online - Umfrage. Deutsches Tierärzteblatt. 2011; 1: 4–9.\n\nDilly M, Ehrich F, Hilke J, et al.: Burnoutgefährdung im Studium der Tiermedizin. German Medical Science GMS Publishing House; 2014.\n\nBrandt JC, Bateman SW: Senior veterinary students’ perceptions of using role play to learn communication skills. J. Vet. Med. Educ. 2006; 33(1): 76–80. PubMed Abstract | Publisher Full Text\n\nHarling M, Strehmel P, Nienhaus A: Stressbelastung und Substanzgebrauch bei Tiermedizinern. Deutsches Tierärzteblatt. 2007; 55(2): 148–159.\n\nLundberg J: Hilfe statt Strafe: Interventionsprogramm (IVP) für substanzabhängige Tierärzte. Deutsches Tierärzteblatt. 2011; 8: 1026.\n\nBartram DJ, Sinclair JMA, Baldwin DS: Alcohol consumption among veterinary surgeons in the UK. Occup. Med. (Lond.). 2009; 59(5): 323–326. PubMed Abstract | Publisher Full Text\n\nSlesina W: Arbeitsbedingte Erkrankungen und Arbeitsanalyse: Arbeitsanalyse unter dem Gesichtspunkt der Gesundheitsvorsorge: 69 Tabellen davon 4 als Falttafeln. Stuttgart: Enke; 1987.\n\nManz R: Fragebogen für körperliche, psychische und soziale Symptome. KÖPS. Frankfurt/M: Swets; 1998.\n\nMaslach C, Jackson SE, Leiter MP: Maslach Burnout Inventory: Third edition. Zalaquett CP, Wood RJ, editors. Evaluating stress: A book of resources. S. 191–218.\n\nWHO: Wellbeing Measures in Primary Health Care/The Depcare Project. Copenhagen: 1998.\n\nMohr G, Rigotti T, Müller A: Irritations-Skala zur Erfassung arbeitsbezogener Beanspruchungsfolgen (IS). Göttingen: Hogrefe; 2007.\n\nSiegrist J: Adverse health effects of high-effort/low-reward conditions. J. Occup. Health Psychol. 1996; 1(1): 27–41. PubMed Abstract | Publisher Full Text\n\nSchaarschmidt U, Fischer A: AVEM - Arbeitsbezogenes Verhaltens- und Erlebensmuster.: Zweite überarbeitete und erweiterte Auflage. Frankfurt: Swets & Zeitlinger (Computerform: Mödling b. Wien: Schuhfried.); 2003.\n\nLefèvre S, Kubinger KD: Differentielles Stress Inventar: Handanweisung. Göttingen: Hogrefe; 2004.\n\nSammito S, Böckelmann I: New reference values of heart rate variability during ordinary daily activity. Heart Rhythm. 2017; 14(2): 304–307. PubMed Abstract | Publisher Full Text\n\nKalimo R, Pahkin K, Mutanen P, et al.: Staying well or burning out at work: Work characteristics and personal resources as long-term predictors. Work Stress. 2003; 17(2): 109–122. Publisher Full Text\n\nSammito S, Thielmann B, Seibt R, et al.: S2k-Leitlinie: Nutzung der Herzschlagfrequenz und der Herzfrequenzvariabilität in der Arbeitsmedizin und Arbeitswissenschaft: AWMF-Register Nr.002/042, Klasse: S2k.2014.\n\nTarvainen MP, Lipponen JA, Niskanen JP, Ranta-Aho PO: Kubios HRV (ver. 3.3) User’s Guide. ©Kubios Oy.2019.\n\nBöckelmann I, Sammito S: Herzfrequenzvariabilitätsanalyse in der betriebsärztlichen Praxis. Zbl Arbeitsmed. 2020; 70(6): 269–277. Publisher Full Text\n\nKersebohm JC: Praktiker im Wandel: Untersuchung der Arbeitsbedingungen und Zufriedenheiten praktizierender Tiermediziner in Deutschland (2016).2018.\n\nVeterinärmedizinische Bildungsstätten: Statistik 2019: Tierärzteschaft in der Bundesrepublik Deutschland. Deutsches Tierärzteblatt. 2020; 68(7): 860–870.\n\nBöckelmann I, Seibt R: Methoden zur Indikation vorwiegend psychischer Berufsbelastung und Beanspruchung — Möglichkeiten für die betriebliche Praxis. Z. Arb. Wiss. 2011; 65(3): 205–222. Publisher Full Text"
}
|
[
{
"id": "155838",
"date": "03 Jan 2023",
"name": "Oliver Hirsch",
"expertise": [
"Reviewer Expertise Research Methods",
"Statistics",
"Occupational Medicine",
"Biological 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\nFirst, it should be mentioned that the authors' approach of conducting an occupation-specific study of psychological stress in veterinarians is very important, as it has been shown that there are specific burdens in different medical specialties to which appropriate interventions must be tailored.\nIntroduction\nInformative and generally well-written.\nPlease include more concrete empirical data from prior research, e.g., \"A recently conducted online survey on veterinarians’ suicide risk confirmed an increased prevalence of suicide compared with the general population….\" By how much was the suicide risk increased? Please include a citation in paragraph regarding heart rate variability (HRV).\nObjectives\n\"Further aims are to analyze the causal relationship between workload and health consequences….\" You are performing an observational study but you want to analyze a causal relationship. This is a contradiction. Please elaborate on this.\nStudy design\n\"the nationwide survey should avoid a selection bias\" How do you ensure this? Do you have membership data of a professional organisation with which you can compare certain characteristics of your sample, e.g., gender and age distributions?\nAll questionnaires used must be described much more precisely (rationale for their selection, their structure, test-theoretical quality criteria such as reliability and validity), also including MIGA-Heart questionnaire and Differential Stress Inventory (DSI). Were there any preliminary studies with these questionnaires in the veterinary area or comparable areas?\nSample size calculation\nYou intended to also analyze other demographic factors like working environment (big city, small town, rural area). How are they incorporated in the sample size calculation? I propose to consider alternative analyses like Partial Least Squares Structural Equation Modeling (PLS-SEM).\nPlease explain further sample size calculation for Part B (minimum n=20?).\nData analysis\n\"missing values being excluded\" Missing value analysis and imputation should be considered. There is a sound empirical basis that just excluding missing values induces bias.\nThe description of the intended statistical data analyses should be more concrete. The authors state \"and will take into account the possible influencing factors such as age, gender, own educational and occupational biography, working environment (big city, small city, rural area) and German state, and their influences on the employees’ health\". How specifically should this be done? Simply listing procedures is unfortunately not sufficient. I refer again to the possibility to consider other analysis methods (e.g. PLS-SEM).\nStudy status\nWhy is the study protocol to be published while the study has already started and not in advance?\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": []
},
{
"id": "213138",
"date": "19 Oct 2023",
"name": "Rachel Dale",
"expertise": [
"Reviewer Expertise Veterinarian suicidality",
"quantitative statistics",
"public mental 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\nResearch clearly shows that mental illness is an urgent topic in the veterinary profession and therefore studies like these are very important. I'm am pleased to see such research underway.\n\nThe methods are sound and appropriate to answer the research question. I particularly find the inclusion of objective HRV measures to be a strength. I find the writing style to be a weakness in the paper and this can be considered for future manuscripts.\nHowever, I’m a little confused as protocols should be submitted prior to data collection but the research was conducted in 2021/2022. Therefore submission of a protocol paper is no longer appropriate. Since the data have already been collected and therefore potentially could have impacted the questions set-out here, I have to recommend that indexing of a protocol paper is no longer appropriate.\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? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-42
|
https://f1000research.com/articles/11-40/v1
|
13 Jan 22
|
{
"type": "Clinical Practice Article",
"title": "Thromboembolic events during neoadjuvant chemotherapy in muscle invasive bladder cancer – any correlation to the central venous access? A clinical practice article",
"authors": [
"Victoria Eriksson",
"Elisabeth Eriksson",
"Amir Sherif",
"Victoria Eriksson",
"Elisabeth Eriksson"
],
"abstract": "Patients with muscle invasive bladder cancer have a generally known 5-year overall survival of approximately 58% with neoadjuvant chemotherapy (NAC). During the last decades, addition of Cisplatinum-based NAC in fit patients prior to radical cystectomy (RC), has significantly improved OS, compared to RC only. However, some published studies following NAC addition, describe an intermediate risk increase of thromboembolic events (TEEs). Placement of central venous access (CVA) before NAC has also been suggested as being a potential risk factor for thrombosis. We present a combination of images and cases from the Northern Swedish health region where three patients developed venous TEE after CVA placement for NAC-administration and found that the time until curable RC was prolonged circa one month each, with an addition of one RC cancelled. These are serious events and to our knowledge, there are no current guidelines on prevention of TEE before RC. The aim with this report was to provide examples of these events and conclude that further prospective trials are warranted on prevention and future guidelines regarding venous anticoagulant treatment for TEE that occur pre-RC in NAC-patients.",
"keywords": [
"Cystectomy",
"Thromboembolism",
"Urinary Bladder Neoplasm",
"Neoadjuvant Therapy",
"Central Venous Access"
],
"content": "Introduction\n\nMuscle invasive bladder cancer (MIBC) accounts for circa 25% of all urinary bladder cancer. The 5-year overall survival (OS) is approximately 58% after three cycles of cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).1 Both NAC and the risk of thromboembolic events (TEEs) has increased during the last decades. Evidence suggests that chemotherapy, in combination with the already hypercoagulable state induced by cancer, could contribute to thrombosis.2,3 It has also been suggested that placement of central venous access (CVA) before NAC could initiate thrombosis as well, with the potential mechanism being endothelial injury of veins.4 In a recent randomized controlled trial, it is also suggested that a much smaller caliber vein, where a CVA in the form of a peripherally inserted central catheter-line (PICC) is inserted, could be related to the risk of the device causing venous thrombosis. A five times higher risk (11%) of thrombosis from PICC-line was seen compared to (2%) the risk from totally implanted (PORTs), which are directly inserted in larger vessel, either the jugular or subclavian vein.5 To our knowledge, there are no clear guidelines on prevention of venous TEE during NAC before cystectomy. We report on three male patients with MIBC from the Swedish Northern health region, who all developed venous TEE after CVA placement, during NAC. The uniqueness of the report includes a combination of clinical information, images and existing sources on the subject presented here in a combined format.\n\n\nCase 1\n\nA 71-year-old Caucasian, male patient presented with gross hematuria. His medical history included ischemic heart disease, anti-platelet medication and prostatectomy due to prostate cancer 10 years prior to the hematuria. His previous occupation was a laborer within the steel industry before retirement. He was staged cT3N0M0 after transurethral resection of bladder (TURB) and received a PICC-line via the basilic vein in the right arm, prior to first NAC-cycle with methotrexate/vinblastine/Adriamycin/cisplatin (MVAC). Within two weeks he developed neutropenic fever, septic infection and chest pain correlated to deep breathing. A computed tomography (CT) pulmonary angiogram (CTPA) displayed multiple pulmonary embolism (PE) on a lobar artery level, to the right middle and inferior lobe (Figure 1A,B). Physical examination showed no sign of swelling in upper or lower extremities and he remained respiratory and circulatory stable. He received venous anticoagulant treatment with anti-Xa; Tinzaparin, with a daily dosage of 16000 IE (equivalent to 144 mg) for a predetermined period of six months. He received the last NAC-cycle and the RC one month delayed (Table 1). According to the most recent follow-up the patient remains in remission (Table 1).\n\n(A) CTPA of our first patient. PE was seen in the right lung on a lobar artery level, to the middle and inferior lobe. (B) Enhancement of PE in (A).\n\nDate of diagnosis; muscle invasive bladder cancer. Age of diagnosis. cTNM stage (clinical tumor-node-metastasis). Histopathology of tumor. Smoking history in pack-years. Types of neoadjuvant chemotherapy (NAC); methotrexate/vinblastine/Adriamycin/cisplatin (MVAC), fluorouracil/mitomycin (FUMI). Number of NAC-cycles. Time from first cycle to thromboembolic event (TEE). Type of TEE. Anti-Xa Treatment; type of antithrombotic medication. Time from first NAC-cycle to radical cystectomy (RC). Radical cystectomy (RC) delayed due to TEE. pTNM stage (pathological tumor-node-metastasis: response outcome of primary tumor; stable disease; pT2-T4aN0M0, partial response; pTa, pTis, pT1.\n\n\nCase 2\n\nA Caucasian, male patient aged 74, also presenting with gross hematuria, had anti-platelet medication due to ischemic stroke in 2018, and a well-treated HIV-infection. Before retirement, he had worked for a large telephone company. The tumor was staged cT2N0M0 and he also received PICC-line via the right basilic vein and MVAC. A routine CT-scan after two cycles displayed multiple PE in the right lung (Figure 2A). The patient had symptoms of fatigue and shortness of breath, but he was respiratory and circulatory stable and physical examinations showed no signs of swelling in upper or lower extremities. He received treatment with anti-Xa; Tinzaparin at the dosage of 16000 IE to be evaluated during a period of six months. Due to deteriorated health, RC was cancelled and alternative curable treatment was recommended from a multidisciplinary conference, including urologist and oncologist. The last MVAC cycle was replaced by fluorouracil/mitomycin to be followed by radical radiotherapy. Initial dosage was 2 Gray, increased gradually to target dose of 68 Gray during 34 sessions under a period of 50 days. Follow-up CTPA after two months detected no residual PE, but the initial symptoms persisted up to a year post-TEE. According to the most recent follow-up the patient remains in remission (Table 1).\n\n(A) CT chest of our second patient, with PE displayed in the right lung. (B) CT chest of our third patient, with a saddle PE displayed centrally, peripherally.\n\n\nCase 3\n\nA Caucasian male aged 69, was admitted due to suspected prostate cancer, but TURB revealed MIBC stage cT3N0M0. He had type 2 diabetes and essential hypertension. He worked in agriculture prior to retirement. The patient also received PICC-line via the right basilic vein and MVAC. After the second cycle, he developed neutropenic fever and back pain. CT scan displayed a centrally peripheral saddle PE (Figure 2B). Physical examination showed no sign of swelling in upper or lower extremities and besides symptoms such as fever, fatigue and pain, he was respiratory and circulatory stable. He received treatment with anti-Xa; Tinzaparin with the dosage of 12000 IE (equivalent to 192 mg) for a predetermined period of six months. He was fit to continue his third MVAC cycle one week post-TEE but RC was ultimately delayed one month. According to the most recent follow-up the patient remains in remission (Table 1).\n\n\nDiscussion\n\nOur patients all received TEE of venous type; PE within 12-30 days after CVA (Table 1). Evidence that NAC could be a contributing factor for thrombosis has been suggested.2,3 Significant higher TEE ORs before RC were seen in NAC-patients compared to NAC-eligible NAC-naïve.4 In Zareba et al, TEEs had connection with CVA and preoperative TEE was associated with shorter OS (Hazard ratio 3.26; 95% confidence interval:1.12–9.44; p = 0.03). NAC-patients also had a 3-fold higher incidence of TEE than NAC-naïve.3 In addition, there is a 70-fold higher risk of TEE during cancer in general.2 A potential connection between TEE and the placement of CVA with following endothelial damage has also been proposed by previous studies.3,4 In a recent randomized controlled trial, it is also suggested that a smaller caliber vein, where PICC-line is inserted, could be related to a five times higher risk of having venous thrombosis from the device, compared to from a CVA of totally implanted (PORTs), which are directly inserted in larger vessel. Recommendations are to use PORTs rather than PICC-line on NAC-patients. PICC-line is however less staff-demanding and more common.5 To our knowledge, there are no current guidelines on prevention of TEE before RC, even though evidence suggests that incidental TEE of venous origin can cause significant mortality and morbidity without proper treatment. The time from diagnosis to RC was significantly longer among NAC-patients compared to NAC-naïve (p < 0.001).3 Our patients had similar delays, including one cancelled RC (Table 1). Prolonged time from diagnosis to RC could potentially allow metastatic dissemination. Our first and second patient had anti-platelet medication prior to diagnosis, but none had specific venous anticoagulants such as anti-Xa. Studies on whether prophylaxis on thrombosis during NAC can reduce the risk of TEE or not, have shown conflicting results.2,3 But in patients with pancreatic cancer, dalteparin achieved an 85% risk-reduction from a 23% TEE incidence rate to 3.4%.2\n\n\nConclusion\n\nEvidence from literature suggests that NAC and malignancy increase the risk for TEE in MIBC-patients. CVA induced thrombosis during NAC, from endothelial damage or insertion in small caliber veins, has also been suggested as a potential mechanism for TEE. There are no current guidelines on prophylactic venous anticoagulation treatment and results from previous studies are conflicting. Time before curable operation can be prolonged if TEE arises. Further prospective trials are warranted on prevention and for developing future guidelines pre-RC regarding TEE in NAC-patients.\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 clinical details and images were specifically obtained from the patients included in this report.",
"appendix": "References\n\nSherif A, Holmberg L, Rintala E, et al.: Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol. 2004 Mar; 45(3): 297–303. PubMed Abstract | Publisher Full Text\n\nDuivenvoorden WC, Daneshmand S, Canter D, et al.: Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy. J Urol. 2016 Dec; 196(6): 1627–1633. PubMed Abstract | Publisher Full Text\n\nZareba P, Patterson L, Pandya R, et al.: Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy. Urol Oncol. 2014 Oct; 32(7): 975–980. PubMed Abstract | Publisher Full Text\n\nOttosson K, Pelander S, Johansson M, et al.: The increased risk for thromboembolism pre-cystectomy in patients undergoing neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer is mainly due to central venous access: a multicenter evaluation. Int Urol Nephrol. 2020 Apr; 52(4): 661–669. PubMed Abstract | Publisher Full Text\n\nMoss JG, Wu O, Bodenham AR, et al.: Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial. Lancet. 2021 Jul 31; 398(10298): 403–415. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "143992",
"date": "12 Jul 2022",
"name": "Katsuhiro Ito",
"expertise": [
"Reviewer Expertise Urology"
],
"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 case series to report the three patients with pulmonary thrombosis during neoadjuvant chemotherapy for urothelial carcinoma. All three patients had a central venous catheter, which the authors considered to be the cause of the emboli. This is an informative paper to raise the caution of the embolic event during the neoadjuvant phase.\n\nMy suggestion was as follows.\nWhy not check the venous thrombus around the catheter and in the leg vein via CT or ultrasound. The physical examination can not rule out the existence of a thrombus. If a massive thrombus remains, the management will be changed.\n\nBMI, performance status, Hb, platelet, leucocyte, and in-hospital/ambulant setting are well-known risk factors and should be described.\n\nAlthough there are no specific guidelines on the prevention of thromboembolism for NAC (neoadjuvant chemotherapy) before radical cystectomy. The guidelines showed that generally, patients with a high risk of thrombosis should receive prophylaxis before chemotherapy (1). The author should mention it.\n\n\"But in patients with pancreatic cancer, dalteparin achieved an 85% risk-reduction from a 23% TEE incidence rate to 3.4%.2\" The citation in this sentence seems inappropriate and makes readers confused.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-40
|
https://f1000research.com/articles/10-1049/v1
|
15 Oct 21
|
{
"type": "Systematic Review",
"title": "Efficacy safety and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials",
"authors": [
"Bendix Samarta Witarto",
"Visuddho Visuddho",
"Andro Pramana Witarto",
"Henry Sutanto",
"Bayu Satria Wiratama",
"Citrawati Dyah Kencono Wungu",
"Bendix Samarta Witarto",
"Visuddho Visuddho",
"Andro Pramana Witarto",
"Henry Sutanto",
"Bayu Satria Wiratama"
],
"abstract": "Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.",
"keywords": [
"drug safety",
"efficacy",
"hemophilia A",
"human and medicine",
"immunogenicity",
"prophylaxis",
"rurioctocog alfa pegol"
],
"content": "Introduction\n\nHemophilia A is a rare, X-linked recessive, congenital bleeding disorder caused by mutations or defects in the factor VIII (FVIII)-producing genes.1 Those mutations manifest as a congenitally absence or decrease of the FVIII, an important pro-coagulant cofactor in the bleeding hemostasis.2 Hemophilia A occurs more commonly than hemophilia B (in 1 out of 5,000 male live births) and accounts for 80% of overall hemophilia cases.2,3 Hemophilia A may be further classified into mild, moderate, and severe based on the FVIII levels.1 The severe form of hemophilia A is defined as having FVIII levels <1% of normal, while the mild and moderate forms have higher FVIII levels that are approximately 5–50% and 1–5%, respectively.3 Patients with severe hemophilia often present with internal bleeding, especially in the joints and soft tissues. Joint and soft tissue bleeding, along with painful feelings, may restrict patients from their daily activities due to the restriction on their range of motions.3,4 If this bleeding continues without being treated adequately, hemophilic patients could suffer from more advanced complications, including hemophilic arthropathy. This is important since hemophilic arthropathy could negatively affect their quality of life due to the severe joint immobility.3\n\nThe current management of hemophilia A relies on two options: (1) episodic or on-demand FVIII replacement if the patients present with any bleedings to prevent further bleeding or (2) prophylactic FVIII treatment to maintain the FVIII levels and prevent any future bleedings.5 However, the first option was no longer recommended as primary long-term management due to no alteration found in its natural disease course.6 To date, the standard of care for hemophilia A, especially the severe form, still relies on a regular prophylactic intravenous FVIII replacement therapy. Additionally, more than 30% of patients with hemophilia A may develop ‘inhibitors’ or refer to as neutralizing anti-drug antibodies to the standard prophylactic treatment which has high immunogenicity in inducing its formation.3 Thus, extended half-life and safer prophylactic agents may be beneficial in reducing the daily treatment burden, and at the same time, those agents could maintain better clinical presentations and improve the treatment efficacy.7\n\nRecently, rurioctocog alfa pegol (i.e., BAX 855), a third-generation recombinant FVIII (rFVIII) with a modification in its polyethylene glycol (PEG) component, has been developed.8 This modification prolongs the half-life of rFVIII by 1.4–1.5 folds the original rFVIII, thereby reducing the administration frequency and maintaining better bleeding hemostasis of the hemophilic patients.8,9 Yet, to the best of our knowledge, there are no pooled studies assessing the efficacy, safety, and immunogenicity of rurioctocog alfa pegol. Therefore, here, we aim to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol, a newly-developed prophylactic agent, in previously treated patients with severe hemophilia A.\n\n\nMethods\n\nThis systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines.10 A computerized and systematic data searching of relevant studies was conducted in PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost) from inception to 16 February 2021. Keywords were constructed based on Medical Subject Headings (MeSH) terms and other additional terms listed as follows: (“rurioctocog alfa pegol” OR “bax 855” OR “TAK-660” OR “SHP660” OR “adynovate” OR “adynovi”) AND (“hemophilia A” OR “haemophilia A” OR “factor VIII deficiency” OR “factor 8 deficiency” OR “classic hemophilia” OR “classic haemophilia”). Two reviewers searched the literatures independently. Any disagreements were resolved in a consensus involving a third investigator.\n\nStudies were included if the following criteria were met: (1) study design of clinical trial; (2) study population consists of previously treated severe hemophilia A patients with or without healthy subjects as control; (3) rurioctocog alfa pegol as a prophylactic treatment intervention; and (4) the reported outcomes related to the efficacy, safety, and immunogenicity of rurioctocog alfa pegol (annualized bleeding rate [ABR], patients with zero-bleeding during treatment, hemostatic efficacy, adverse events [AEs], number of deaths, development of FVIII ‘inhibitors’, and/or binding antibodies). The exclusion criteria were as follows: (1) irrelevant titles and abstracts; (2) review articles, systematic reviews, meta-analyses, case reports, case series, letter to editors, and conference abstracts; (3) non-English studies; or (4) irretrievable full-text articles.\n\nThe following relevant data were extracted from the included studies: (1) author and year of publication; (2) study location; (3) clinical trial number; (4) study design; (5) total patients included for prophylactic treatment, gender, and age; (6) definition of target joint (TJ); (7) regimen type; (8) patient characteristics (with or without target joints); (9) total patients in per-protocol analysis set (PPAS) or analyzed for ABR based on regimen type and target joints; (10) outcomes related to efficacy (types of ABR, number of patients with zero-bleeding during treatment, and/or hemostatic efficacy); (11) outcomes related to safety (number of patients with AEs, total AEs, AEs considered related to treatment, and/or number of deaths); and/or (12) outcomes related to immunogenicity (development of FVIII ‘inhibitors’ and/or binding antibodies). The quality assessment of the included studies was performed using the Methodological Index for Non-Randomized Studies (MINORS) scale11 for non-randomized studies and Modified Jadad scale12 for randomized studies. Studies with a MINORS score of ≥ 12 or a Jadad score of ≥ 4 were considered high-quality studies, and the rest were considered low-quality studies. The data extraction and quality assessment were conducted by three reviewers collaboratively through a group discussion and a final decision was taken based on the agreement of all reviewers.\n\nStatistical analyses were performed using the latest version of OpenMeta [Analyst] from the Brown University Evidence-Based Practice Center13 and MetaXL ver. 5.3 (EpiGear International, Sunrise Beach, Australia). Single-arm meta-analysis of mean and standard deviation values was performed for four different efficacy outcomes: (1) total ABR; (2) spontaneous ABR; (3) injury ABR; and (4) joint ABR. Whilst, a meta-analysis of proportions was performed for two different efficacy outcomes: (1) zero-bleeding prevalence and (2) hemostatic efficacy with the rating of excellent or good. Subgroup analysis based on target joints (TJs) for total ABR was also performed. For the purpose of meta-analyses, 95% confidence intervals were transformed into standard deviation values based on a method suggested by the Cochrane Handbook Chapter 6.14\n\nHeterogeneity between studies was assessed with a chi-square test (Cochran’s Q statistic) and quantified with the Higgins’ I2 statistic. P-value < 0.1 from the chi-square test indicated statistical heterogeneity, whereas the level of heterogeneity was determined using I2 values. I2 < 25% was considered a low heterogeneity, 25–75% a moderate heterogeneity, and I2 > 75% a high heterogeneity. If the I2 value was greater than 50%, a random-effects model was used for the meta-analysis. Otherwise, a fixed-effects model was applied. Publication bias was explored qualitatively using a funnel plot if the number of studies was adequate (n ≥ 10).\n\n\nResults\n\nThe initial search of this study yielded a total of 232 articles identified from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Of those, 174 studies were screened by titles and abstracts after duplicates removal. Twenty-three were fully reviewed based on the eligibility criteria and 19 of these were excluded due to: (1) studies with a sub-analysis of other included studies (n = 2); (2) not reporting the outcome of interest (n = 7); or (3) conference abstracts (n = 10). Finally, four clinical trials5,7,9,15 were included in the qualitative and quantitative synthesis. The overall study selection process is illustrated in Figure 1.\n\nPRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.\n\nTable 1 provides a summary of the studies included in the systematic review. The four uncontrolled clinical trials5,7,9,15 included a total of 517 previously treated severe hemophilia A patients for prophylactic treatment, with the overall mean ± SD age of 23.9 ± 14.8. Only two studies by Mullins et al.9 and Chowdary et al.7 included a female patient. The trials were published between 2015 and 2021 and were all multicentered with a range number of 11 to 23 countries. Three7,9,15 out of four studies were in phase 3 clinical trial, whereas the study by Konkle et al.5 was in a phase 2/3 trial. All studies were non-randomized with the exception of Klamroth et al.15 Definition of target joint was the same across all studies, except for Klamroth et al.15 There were two different prophylactic regiment types used between studies: twice-weekly and pharmacokinetic (PK)-guided. The “excellent” hemostatic efficacy rating was defined as a complete resolution of pain and sign of bleedings after a single infusion without the requirement of additional infusion to control the bleeding, while the “good” rating was defined when there was a definite improvement in pain and/or signs of bleeding after a single infusion with a possible requirement of more than one infusion to complete the resolution. The “fair” rating was defined as a slight improvement in pain and/or signs of bleeding after a single infusion with definite requirement of more than one infusion to complete the resolution. If there was no improvement or the condition worsen, the hemostatic efficacy was rated “none”.5\n\nCharacteristics of the included studies.\n\n\n\n• 16 developed binding antibodies to FVIII, PEG-FVIII, or PEG prior to exposure, but turned negative while on treatment\n\n• 5 developed antibodies to PEG-VIII during treatment (2 were transient; 2 were only at study completion; and 1 was with decreasing titre)\n\n• No development of persistent binding antibodies that affected efficacy or safety\n\n\n\n• 5 developed binding antibodies to FVIII\n\n• 8 developed binding antibodies to PEG-FVIII\n\n• Only one persisted to the study end without any notable safety or efficacy findings\n\n\n\n• 7 developed transient binding antibodies to PEG-FVIII or FVIII\n\n• No subjects developed persistent binding antibodies to FVIII, PEG-FVIII, or PEG\n\n• Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs\n\n\n\n• 3 had single positive binding antibodies to PEG-FVIII and PEG at baseline only\n\n• Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs\n\n\n\n• 8 developed transient binding antibodies to PEG-FVIII or FVIII.\n\n• Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs\n\n* Data are presented in mean ± SD.\n\nTotal ABR\n\nA total of 473 hemophilia A patients from the four studies5,7,9,15 were included in this subgroup single-arm meta-analysis (Figure 2) to calculate the pooled mean of total ABR after rurioctocog alfa pegol treatment. A random-effects model was used for the analysis since heterogeneity among studies was greater than 50% (I2 = 67%). The overall pooled mean of total ABR was 2.59 (95% CI = 2.04–3.14).\n\nABR, annualized bleeding rate; CI, confidence interval; PK, pharmacokinetic; TJ, target joint.\n\nTwo studies5,9 reporting mean of total ABR individually for patients with target joints (TJs) and without target joints were included in Subgroup 1 and Subgroup 2, respectively. The pooled mean of total ABR in patients with TJs was 3.21 (95% CI = 1.87–4.54), whilst the pooled mean of total ABR in patients without TJs was 3.33 (95% CI = 2.56–4.09). Subgroup 3 included other two studies7,15 with a combined mean of total ABR for patients with and without TJs. The pooled value was 2.21 (95% CI = 1.57–2.84).\n\nSpontaneous ABR\n\nThe four studies5,7,9,15 with a total of 473 hemophilia A patients were included in this meta-analysis (Figure 3A). Heterogeneity between studies was greater than 50% (I2 = 64%); therefore, a random-effects model was used for the analysis. The result of the pooled mean of spontaneous ABR was 1.24 (95% CI = 0.91–1.58).\n\nInjury ABR\n\nA total of 161 hemophilia A patients from two studies9,15 that reported mean of injury ABR were included in this meta-analysis (Figure 3B). A random-effects model was used for the analysis since heterogeneity was greater than 50% (I2 = 80%). The pooled mean of injury ABR was 1.26 (95% CI = 0.53–1.99).\n\nJoint ABR\n\nA total of 473 hemophilia A patients from the four studies5,7,9,15 were evaluated in this subgroup analysis of joint ABR (Figure 3C). The heterogeneity across studies was low (I2 = 0%); therefore, a fixed-effects model was used for the analysis. The pooled mean of joint ABR was 1.31 (95% CI = 1.12–1.50).\n\nABR, annualized bleeding rate; CI, confidence interval; PK, pharmacokinetic; TJ, target joint.\n\nZero-bleeding prevalence\n\nAll four studies5,7,9,15 were included in this meta-analysis of zero-bleeding prevalence (Figure 4A). A random-effects model was used due to the heterogeneity of the data (I2 = 88%). The pooled prevalence result was 40% (95% CI = 27%–54%).\n\nCI, confidence interval; PK, pharmacokinetic.\n\nHemostatic efficacy\n\nThree studies5,7,9 that reported hemostatic efficacy with the rating of excellent or good were included in this meta-analysis (Figure 4B). A random-effects model was used due to the heterogeneity across studies (I2 = 93%). The pooled hemostatic efficacy was 92% (95% CI = 85%–97%).\n\nA total of 1,299 non-serious adverse events (non-SAEs) occurred during the four studies.5,7,9,15 However, only 30 (2.3%) of them were considered related to rurioctocog alfa pegol treatment. Whilst, a total of 70 serious adverse events (SAEs) were observed in the four studies and only one (1.4%) of them – as reported by Klamroth et al.15 – were considered related to treatment. Among all studies, only one death case was reported by Chowdary et al.7 and was not considered to be related to rurioctocog alfa pegol treatment.\n\nThree studies5,7,9 reported no development of FVIII inhibitory antibodies among all patients. Klamroth et al.15 reported one patient with development of FVIII inhibitory antibodies and was resolved at the end of the study. Development of binding antibodies to either FVIII, PEG-FVIII, or PEG among patients was detected in 52 patients from the four studies. However, none of them was correlated to impaired rurioctocog alfa pegol treatment efficacy and AEs.\n\nPublication bias using funnel plot was not performed due to the low number of the included studies. Details of the quality assessment using MINORS and Modified Jadad scale are provided in Table 2. All non-randomized studies5,7,9 were considered high in quality, whereas the randomized study by Klamroth et al.15 was considered low in quality.\n\n\nDiscussion\n\nThis study was the first far-reaching, single-arm meta-analysis that evaluates the efficacy, safety, and immunogenicity of rurioctocog alfa pegol, a newly developed rFVIII product with a prolonged half-life, as a prophylactic treatment for previously treated patients with severe hemophilia A. Rurioctocog alfa pegol (BAX 855) is a pegylated full-length rFVIII product designed to reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy in patients with hemophilia.16,17 This study indicated the long-term safety and efficacy of the pharmacological agent, which were consistent with the study of rurioctocog alfa pegol for perioperative hemostasis in hemophilia A patients,18,19 also with the previous parent studies.20–22\n\nThe overall pooled mean of total ABR of rurioctocog alfa pegol is lower compared to the several conventional rFVIIIs (Advate®, Xyntha®, Novoeight®, REFACTO®) with their total ABR ranged from 3.3 to 6.5.23 This could indicate that rurioctocog alfa pegol has advantages over conventional recombinant antihemophilic FVIII. The ABRs were also similar for spontaneous and injury-related bleeding. Any reduction in joint bleeds is considered an improvement in quality of life for hemophilia patients.24 Decreased bleeding in joints thereby shows better joint health, activity, and satisfaction for the patients.25 The mean ABR for patients with target joints was similar to those without target joints, indicating that rurioctocog alfa pegol had an equal efficacy for both groups of patients. Moreover, all studies reported that rurioctocog alfa pegol had higher good and excellent hemostatic efficacy events. This data was comparable with results reported for other rFVIII preparations.26–29 The efficacy of rurioctocog alfa pegol was also supported by the finding on the pooled zero-bleeding prevalence.\n\nOur study also demonstrated the safety of rurioctocog alfa pegol in patients by assessing the non-SAEs and SAEs. Rurioctocog alfa pegol was also proven to be acceptable and safe for perioperative hemostasis in patients with hemophilia A, with minor findings in both non-SAEs and SAEs.18 Our data showed that most of the adverse reactions were mild. Additionally, rFVIII usage decreased the risk of blood-borne infections and restored longer life expectancies.30 This extended half-life recombinant also improved adherence to prophylactic regimen and reduced the burden of treatment.31,32\n\nThe development of FVIII ‘inhibitors’ is a major issue in patients treated with blood coagulation factor products. The development of neutralizing alloantibodies against FVIII can reduce the treatment benefits.33,34 Currently available studies revealed some predictors of ‘inhibitor’ development, but the predictive power remained low.35,36 Some studies also reported either transient or persistent ‘inhibitor’ development in patients treated with plasma-derived FVIII.37,38 However, our findings showed no development of persistent FVIII inhibitory antibodies, and this was consistent with the US Food and Drug Administration's approval of rurioctocog alfa pegol for the treatment of hemophilia A patients.39 There was some development of binding antibodies observed. However, this development did not interfere with rurioctocog alfa pegol treatment safety and efficacy until the end of the study.\n\nOverall, our study successfully demonstrated the pooled efficacy, safety, and immunogenicity of rurioctocog alfa pegol as a treatment for hemophilia A. These results can be used to plan an alternative treatment for hemophilia A patients. Nevertheless, high heterogeneity existed between the included studies. We used the random-effects model to minimize this issue. Substantial efforts were made to explore the possible source for heterogeneity, revealing that different dose regimens and prior prophylactic drugs for treatment could be responsible for the high heterogeneity. Regarding the zero-bleeding prevalence (Figure 4A), a difference was observed among studies that employed different dose regimens. Different dose regimens were considered because pharmacokinetic profiles, targets of FVIII level, and age group varied among patients.6\n\nSeveral other limitations exist in this meta-analysis. First, our study only included single-arm clinical trials. The highest possible quality cannot be ensured due to the lack of control arms. However, since hemophilia is a rare genetic disease, comparison with a control arm receiving prophylaxis with other conventional FVIII products was not recommended, as stated by the regulatory guide.40 Second, diverse prior prophylactic strategies in the patients before switching to rurioctocog alfa pegol may affect the treatment outcomes. Finally, only a few published studies were evaluated in this meta-analysis since rurioctocog alfa pegol is a newly-developed drug. However, these limitations were partly compensated by the multicentered settings of the included studies.\n\n\nConclusions\n\nOur study suggests that rurioctocog alfa pegol is effective, safe, and has low immunogenicity for previously treated patients with severe hemophilia A. Despite the lack of direct comparison studies, rurioctocog alfa pegol could serve as an alternative bleeding prophylaxis in hemophilia A. A network meta-analysis with a multi-arm approach on hemophilia A treatment is warranted to corroborate the current evidence.\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\nReporting guidelines\n\nOpen Science Framework: PRISMA Checklist for “Efficacy, Safety, and Immunogenicity of Rurioctocog Alfa Pegol for Prophylactic Treatment in Previously Treated Patients with Severe Hemophilia A: A Systematic Review and Meta-Analysis of Clinical Trials”. http://doi.org/10.17605/OSF.IO/7MNRP.41\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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Publisher Full Text\n\nSchrijvers LH, Uitslager N, Schuurmans MJ, et al.: Barriers and motivators of adherence to prophylactic treatment in haemophilia: A systematic review. Haemophilia. 2013; 19(3): 355–61. PubMed Abstract | Publisher Full Text\n\nSantagostino E, Young G, Carcao M, et al.: A contemporary look at FVIII inhibitor development: still a great influence on the evolution of hemophilia therapies. Expert. Rev. Hematol. 2018; 11(2): 87–97. PubMed Abstract | Publisher Full Text\n\nGaragiola I, Palla R, Peyvandi F: Risk factors for inhibitor development in severe hemophilia a. Thromb. Res. 2018; 168(March): 20–7. PubMed Abstract | Publisher Full Text\n\nSpena S, Garagiola I, Cannavò A, et al.: Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement. J. Thromb. Haemost. 2018; 16(4): 778–90. 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PubMed Abstract | Publisher Full Text\n\nU.S. Food and Drug Administration (FDA): Adynovate [Bula].2016; 1–27.\n\nEuropean Medicines Agency: Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products Table of contents.2012.Reference Source.\n\nWitarto BS, Visuddho V, Witarto AP: PRISMA Checklist for “Efficacy, Safety, and Immunogenicity of Rurioctocog Alfa Pegol for Prophylactic Treatment in Previously Treated Patients with Severe Hemophilia A: A Systematic Review and Meta Analysis of Clinical Trials.”2021. Publisher Full Text"
}
|
[
{
"id": "97267",
"date": "02 Nov 2021",
"name": "Yelvi Levani",
"expertise": [
"Reviewer Expertise Immunology"
],
"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 is clearly written and well organized. This paper presented the meta analysis of the efficacy, safety and immunogenicity of newly developed drug for severe hemophilia A, rurioctocog alfa pegol. The figures and tables are also clear and helpful.\nHowever, there are some parts that need clarifying:\nIn the result part (section: safety outcomes) the author stated: \"A total of 1,299 non-serious adverse events (non-SAEs) occurred during the four studies.5,7,9,15 However, only 30 (2.3%) of them were considered related to rurioctocog alfa pegol treatment. Whilst, a total of 70 serious adverse events (SAEs) were observed in the four studies and only one (1.4%) of them – as reported by Klamroth et al.15 – were considered related to treatment\" - I think it would be nicer, if author gives more explanation or examples about what kind of serious adverse that related to rurioctocog alfa pegol treatment.\n\nIn the discussion part, the author stated, \"Regarding the zero-bleeding prevalence (Figure 4A), a difference was observed among studies that employed different dose regimens. Different dose regimens were considered because pharmacokinetic profiles, targets of FVIII level, and age group varied among patients.\" - I think it would be better if the authors explain more about the dose regimens and pharmacokinetic in the introduction or discussion part.\nI added a reference from Stidl et aI. (2018)1, because the article explained about the safety and potential adverse effects that related to rurioctocog alfa pegol. This reference could help enrich the discussion of article, especially in the part of safety and adverse effects from the drug.\nOverall, this article is interesting and gives valuable information.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "7391",
"date": "11 Nov 2021",
"name": "Citrawati Wungu",
"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. We hereby list the responses and revisions made on the original manuscript: 1. In the result part (section: safety outcomes) the author stated: \"A total of 1,299 non-serious adverse events (non-SAEs) occurred during the four studies.5,7,9,15 However, only 30 (2.3%) of them were considered related to rurioctocog alfa pegol treatment. Whilst, a total of 70 serious adverse events (SAEs) were observed in the four studies and only one (1.4%) of them – as reported by Klamroth et al.15 – were considered related to treatment\" - I think it would be nicer, if author gives more explanation or examples about what kind of serious adverse that related to rurioctocog alfa pegol treatment. Answer: Thank you for the suggestion. We have added an additional information regarding the serious adverse event occurred related to the treatment as reported by Klamroth et al.15 in the safety outcomes section of the result part. 2. In the discussion part, the author stated, \"Regarding the zero-bleeding prevalence (Figure 4A), a difference was observed among studies that employed different dose regimens. Different dose regimens were considered because pharmacokinetic profiles, targets of FVIII level, and age group varied among patients.\" - I think it would be better if the authors explain more about the dose regimens and pharmacokinetic in the introduction or discussion part. Answer: We have provided further explanation regarding the dose regimens and pharmacokinetic in the discussion part. We would also like to revise and correct the structure of the mentioned sentences to avoid unclarity. 3. I added a reference from Stidl et aI. (2018)1, because the article explained about the safety and potential adverse effects that related to rurioctocog alfa pegol. This reference could help enrich the discussion of article, especially in the part of safety and adverse effects from the drug. Stidl R, Denne M, Goldstine J, Kadish B, et al.: Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated (rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety.Pharmaceuticals (Basel). 2018; 11 (3). PubMed Abstract | Publisher Full Text Answer: Thank you for the recommendation. We have added an additional description related to safety based on the suggested reference."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1049
|
https://f1000research.com/articles/10-1090/v1
|
27 Oct 21
|
{
"type": "Research Article",
"title": "The post-pandemic era: will physical distancing be a perceived way of life?",
"authors": [
"Soban Qadir Khan",
"Jehan Al-Humaid",
"Faraz Ahmed Farooqi",
"Mohammed M. Gad",
"Muhanad Al-Hareky",
"Faisal Al-Onaizan",
"Fahad A. Al-Harbi",
"Jehan Al-Humaid",
"Faraz Ahmed Farooqi",
"Mohammed M. Gad",
"Muhanad Al-Hareky",
"Faisal Al-Onaizan",
"Fahad A. Al-Harbi"
],
"abstract": "Background: This study aimed to determine whether people living in the Eastern Region of Saudi Arabia would prefer to continue the practice of physical distancing after the coronavirus disease 2019 (COVID-19) pandemic or to return to their previous way of life.\nMethods: This cross-sectional study was conducted from August 2020 to October 2020 in the Eastern Region of Saudi Arabia. A pre-tested questionnaire was sent electronically through social media. Data on participants’ demographics and their perspectives regarding post-pandemic physical distancing were collected. The calculated sample size was 1,066; however, the total number of responses included in the analysis was 989.\nResults: The average age of the participants was 31.15±11.93 years. There were 435 men and 554 women in the study. Participants showed significantly high levels of disagreement with statements indicating that they were willing to use public transportation (61%), attend social gatherings (36%), and hug relatives or colleagues (40%) after the pandemic (p<0.001); however, 43% agreed that they would spend time with family or friends (p<0.001). The level of education was also found to be significantly related to the responses, and the level of disagreement increased as the level of education increased (p<0.001).\nConclusions: One-third of the study participants planned to continue engaging in physical distancing even after the current pandemic. This clearly indicates that our lives are not returning to how they were before the pandemic. However, it cannot be concluded whether or not this behavior will prevail in the long run. If so, it may greatly affect some businesses and perhaps some social norms and values as well.",
"keywords": [
"COVID-19",
"Post-pandemic",
"Lifestyle",
"physical distancing",
"Coronavirus",
"Saudi Arabia"
],
"content": "Introduction\n\nThe novel coronavirus (coronavirus disease 2019 [COVID-19]) belongs to the same family of viruses (coronaviruses) as the Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV).1,2 Many respiratory viruses are believed to transmit over multiple routes, including droplets, aerosols, and fomites.4 Respiratory droplets moving from one person to another and contact with contaminated surfaces and objects are the primary sources of transmission.5,6 Presymptomatic transmission is the second type of transmission, in which the virus is transmitted from an infected person who has yet to develop symptoms to another person.7\n\nThe effectiveness of physical distancing is determined by individual behavior.8 The interventions most essential for control of pandemics necessarily disrupt social processes. Public measures were implemented in response to COVID-19; people were encouraged by authorities, media, and peers to voluntarily adopt “personal distancing” behaviors to reduce virus transmission (e.g., avoiding physical contact or close proximity with non-household members and reducing use of shared public spaces).9\n\nVarious guidelines have been issued to reduce the spread of the pandemic, including avoiding handshaking or any type of physical contact, avoiding social gatherings or visiting family or friends, wearing masks and gloves, closure of public venues, and tourism and travel restrictions.2 Increasing handwashing, minimizing face touching, wearing masks in public, and physical distancing are the measures that have been adopted globally.1 Because COVID-19 returns in waves, the psychological impacts of physical distancing will persist over time and may indeed become accentuated with repeated iterations of physical distancing. Given that physical distancing affects the types of activities in which one can engage and impacts how activities are carried out, it is likely that this accounts for some of the psychological impact.10\n\nNonverbal communication involves sending or receiving information without words. This form of communication is used across the globe; however, its usage varies from country to country. Cultures can be categorized as “high-context” or “low-context.” High-context cultures rely heavily on nonverbal communication, and low-context cultures rely little on nonverbal communication.11 The present study population consisted of people living in Saudi Arabia, a Middle Eastern country, and Saudi society can be classified as a “high-context culture.” Saudi people rely heavily on nonverbal communication, such as kissing and hugging as a greeting or welcome and as a sign of respect.12 In contrast, physical distancing measures can feel unnatural11,13; however, regular practice of certain behaviors over a long period of time can make them automatic or habitual.14 In addition, people are becoming comfortable with limiting socialization and following precautionary measures due to the secondary reinforcement gained as a consequence.13,15 To the best of our knowledge, the literature has yet to consider the possible post-pandemic-era lifestyles and behaviors of the people living in the Eastern Region of Saudi Arabia. Therefore, this study aimed to determine whether people living in the Eastern Region of Saudi Arabia would prefer to continue the practice of physical distancing after the coronavirus disease pandemic or to return to their previous way of life.\n\n\nMethods\n\nThis cross-sectional study was conducted in the Eastern Region of Saudi Arabia. The study was conducted from August 2020 to October of 2020. Institutional approval was obtained from the College of Dentistry, Imam Abdulrahman Bin Faisal University (approval number 202162).\n\nThe inclusion criteria were as follows: (1) aged between 18 and 70 years, and (2) residing in the Eastern Region of Saudi Arabia. The exclusion criterion was not being able read and understand English or Arabic. To calculate the sample size, a simple random sampling technique was used, and the size of the sample was calculated using the online software Raosoft (Seattle, Washington, USA). The response distribution was set at 50%, the margin of error was set at 3%, and the confidence interval was set at 95%. The calculated sample size was 1066.\n\nThe questionnaire for the study included questions related to demographics and physical distancing. Precautions and instructions related to physical distancing provided by the World Health Organization and United States Centers for Disease Control, and these precautions were used to develop the items of the questionnaire. Initially, the questionnaire was written in English and translated into Arabic. The English version of the questionnaire was translated into Arabic by an Arabic language expert who was also proficient in English. Then the Arabic version was translated back into English by another expert in both languages. After developing the questionnaire, a pilot study was performed to test the validity of the questionnaire, and the kappa statistic was 0.79.\n\nIn line with COVID-19 precautions, the questionnaire was administered electronically. Questionpro software (Dallas, TX, USA) was used for preparing the survey online. The questionnaire contained a total of 16 questions; however, questions regarding personal identification were not included to keep the responses anonymous. Responses for each item were based on a 5-point Likert scale (1 = “Never,” 2 = “Seldom,” 3 = “Sometimes,” 4 = “Frequently,” 5 = “Always”). To simplify the analysis and presentation of results, the response categories (1 to 5) were grouped into three categories: disagree (after combining never and seldom), neutral (sometimes), and agree (after combining frequently and always). All authors of the study then sent the survey link to all their WhatsApp contacts. The authors also requested from their contacts to share the links further.\n\nThe data were collected in Excel and later transferred to and coded in SPSS version 23 (IBM Corp., Armonk, NY, USA) for analysis. Frequency distributions and bar diagrams were constructed for descriptive analysis and presentation of the data. Normality of the data was tested first using the Shapiro-Wilk test, and the results were nonsignificant, indicating that the data were normally distributed. Hence, parametric tests were used for inferential analysis. A one-sample chi-square test was used to analyze the significance of the proportion of responses for each question. A chi-square test was used to compare participants’ demographics with their responses to questions related to physical distancing. The level of significance was set at P < 0.05.\n\nEthical approval for the research was obtained from the Research Unit of College of Dentistry, Imam Abdulrahman Bin Faisal University. The ethical approval letter number was EA:202162.\n\nA summary of the study was presented at the start of the survey along with a consent statement. Consent was implied by the submission of the completed anonymous survey. Written consent was not appropriate, given the anonymous nature of the survey. Participants had to click on the “Next” button to proceed with the questions, which were all on the participants’ plans with regard to physical distancing behavior after the COVID-19 pandemic.\n\n\nResults\n\nThe current study included 989 participants who completed and submitted the survey. A total of 1,350 individuals started the survey, and 989 completed it, resulting in a response rate of 73.5%. The mean age of the participants was 31.15 ± 11.93 years, with a range of 20 to 61 years. The majority of the participants were Saudi (705 [70%] Saudi participants and 284 [30%] non-Saudi participants). There were 435 (44%) men and 554 women (56%). Most of the participants were undergraduate students 474 (48.1%), followed by graduated 217 (22%), postgraduates 143 (15%) and 150 (15%) were undertaking qualifications at high school level. Overall, 677 (68%) lived with an average of 4 to 6 adults and 2 children.\n\nFigure 1 shows the responses to the post-COVID-19 survey of the entire study population. The percentage of disagreement was highest for the item on using public transportation with strangers, and the difference between disagree and agree was statistically significant (87% vs. 13%) (P < 0.001). Similarly, the percentage of disagreement was significantly higher for the items on attending gatherings of close family/friends/other relatives (72% vs. 28%) (P < 0.001) and greeting family, friends, and colleagues with a hug (71% vs. 29%) (P < 0.001). The highest percentage of agreement among all items was observed for spending time with family or friends (43%), which was significantly high (P < 0.001).\n\nThis section of the questionnaire evaluated participants’ sense of safety in engaging in handshaking and hugging when greeting others after the pandemic (Table 1). Non-Saudi residents were significantly higher in terms of disagreement with the items on handshaking (P < 0.0001) and hugging family or friends during greetings (P < 0.001). Women were less likely to disagree with the items on greeting by hugging than men (36% vs. 45%, P < 0.012). The level of education was found to be significantly associated with participants’ responses (P < 0.0001). There was no significant variation in responses between the size of family with handshaking, but the participants with 1-3 individuals in the home were significantly more likely to disagree with the item on hugging family or friends (P < 0.003).\n\n* Statistically significant at P < 0.05.\n\nTable 2 presents the participants’ responses with regard to their sense of safety in engaging in social activities after the pandemic. Saudi nationals were significantly more likely to agree with the items on spending time with family or friends (49% vs. 27%, P < 0.001), attending family gatherings (33% vs. 16%), hosting gatherings (43% vs. 15%, P < 0.001) and going for picnics or to shopping malls (48% vs. 25%, P < 0.001). Gender was not found to be associated with agreement with the items on engaging in social activities; however, women were significantly more fearful regarding attending public gatherings (P < 0.002). Level of education was found to be significantly associated with agreement with the items on spending time with family or friends, attending or hosting gatherings, and going out for self-enjoyment (P < 0.0001). Families with 4 to 6 people were significantly more likely to agree with the items on engaging in social activities like spending time with friends or family and attending parties (P = 0.001, 0.002 and 0.033, respectively).\n\nNationality had a significant statistical association with agreement with the items on routine activities, such as using public transportation (P = 0.05), attending places of prayer (P = 0.017), and visiting the hospital for checkups or appointments (P = 0.0001) (Table 3). Men were more likely to agree with the item on congregational prayers in religious venues (P = 0.0001). Participants with higher education were less likely to agree with the items on using public transportation (P = 0.013), visiting hospitals or healthcare places for regular checkups, and attending congregational prayer in masjids, churches, or temples (P = 0.005). It was also found that family size was not statistically associated with any of these essential/routine activities (Table 3).\n\n\nDiscussion\n\nAfter the outbreak of the current pandemic, physical distancing was proposed and implemented as a primary method of reducing its spread. Recommended physical distancing measures can be divided into three categories: (1) avoid contact with others (e.g., handshakes and hugs), (2) avoid using or visiting publicly shared places, and (3) avoid participating in religious and non-religious gatherings. Studies evaluating the changes in lifestyle due to restrictions imposed as precautionary measures have been conducted across the globe.16,17 However, the present study was conducted to evaluate the perceived post-pandemic lifestyle.\n\nIn the analysis of the questions related to physical distancing behaviors, it was observed that significantly high percentages of respondents either disagreed with or were neutral about discontinuing the practice of physical distancing. With regard to public transportation, only 13% agreed that they would use public transportation even after the pandemic. This cautious behavior will have a significant impact on the transportation industry. The industry must develop strategies to reduce this impact and plan well for the post-pandemic era. Hao et al., for example, have proposed a disaster management framework and post-pandemic agenda for the hotel industry.18 In the present study, over 70% of participants also showed their disagreement or neutrality when asked about attending gatherings of family and friends, or hugging them. The nature of these three questions (using public transportation, attending gatherings, and giving and receiving hugs) are relevant to many aspects of life after COVID-19; people will be in closed environments and will have more contact with one another. Similarly, as aerosols are known to be the primary method of spreading the virus, people will avoid hugging others.19 Another notable aspect of the study findings was that about one-third of the respondents were unsure about practicing physical distancing after COVID-19. Hence, if they decide later on to stop physical distancing, then the percentage of people who agree will become significantly higher compared with those who disagree (almost 70% vs 30%), or if they keep practicing then the outcome will be the reverse.\n\nParticipants who were Saudi citizens showed more resilient behavior than non-Saudis, and it was found that there was a significantly higher percentage of Saudi citizens who reported wanting to return to their normal ways of life. For almost all questions being asked, the percentage of individuals who wanted to behave as they did before the pandemic was higher among Saudis compared with non-Saudis. These findings may be due to high context non-verbal communication among Arabs12; the other groups of study participants were mostly non-Arabs. Hence, a significant difference in perspectives was observed.\n\nThe purpose of vaccines is to boost the human immune system in order for the body to better fight viruses. This is also true for COVID-19 vaccines.20 Hence, the fear of getting infected or having any COVID-19 positive individual within 2 meters will remain even after the pandemic ends.21 In contrast, the minimum distances that have been maintained between an infected person and a potential host are disputable and are far from being established based on scientific evidence.22 In our study, those who were more educated indicated that they were more likely to continue practicing physical distancing after the pandemic. It may be that educated people are more aware of the virus and its effects even after vaccination or the end of the pandemic.\n\nThe present study had some limitations. First, it was conducted on a large scale, and data were only collected from the Eastern Region of Saudi Arabia. Hence, the study’s findings cannot be generalized to the entire population of the country. Second, this study did not include the religion of the participants, which could be an important factor. Religious factors could have an impact on post-pandemic physical distancing behaviors. Similarly, nationality was just noted as Saudi or non-Saudi, and future studies should examine the specific nationalities of the participants. This would facilitate the analysis and country-wise or region-wise comparison of the data. Finally, the data collection process was completed before the development of the vaccine, after getting vaccinated people may feel safer and their responses may be different.\n\nThe overall impression from the study findings was that practicing physical activities and adopting a normal lifestyle after the pandemic will vary due to cultural and social norms and values. Societies that more commonly use non-verbal communication methods will be more likely to stop practicing physical distancing; however, education level was found to be negatively associated, and hence more educated people perhaps adopt physical distancing even after this pandemic.\n\nTherefore, it can be concluded that fear-related factors will not be eliminated soon after this pandemic. However, engagement in physical activities and the carrying out of normal life after this pandemic will vary due to cultural and social norms and values. It was also observed that people will be either hesitant or avoid closed environments and public transportation, and this will affect some businesses, especially the public transportation sector. Furthermore, it was found that a significantly higher proportion of more educated individuals compared with others will practice physical distancing after the pandemic. Future studies are recommended to evaluate the change in perception of post-pandemic physical distancing after the development of vaccines. In addition, if this perceived lifestyle remains for a long period, it will affect social life, and will have significant consequences on the culture and society.\n\n\nData availability\n\nHarvard Dataverse: Post-Pandemic era: will physical distancing be a perceived way of lifestyle? https://doi.org/10.7910/DVN/IGSGU3.23\n\nThe project contains the following underlying data:\n\n• Final Data Edidted.tab (The data file containing the complete data, which includes demographic variables and responses related to physical distancing behavior).\n\nHarvard Dataverse: Post-Pandemic era: will physical distancing be a perceived way of lifestyle? https://doi.org/10.7910/DVN/IGSGU3.23\n\nThis project contains the following extended data:\n\n• QuestionPro-Survey-7657352-PDF-Export-05-19-2021-T043556.pdf (Questionnaire used for data collection in this study in both English and Arabic).\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\nWei WE, Li Z, Chiew CJ, et al.: Presymptomatic transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. 1 April 2020; 69(14): 411–415. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKimball A, Hatfield KM, Arons M, et al.: Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility — King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 3 April 2020; 69(13): 377–381. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCDC: Coronavirus Disease (COVID-19), Situation Summary. [Accessed 14 April 2020]. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/summary.html\n\nWang J, Du G: COVID-19 may transmit through aerosol. Ir J Med Sci. 2020 24 March; 189(4): 1143–1144. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu J, Liao X, Qian S, et al.: Community transmission of severe acute respiratory syndrome coronavirus 2, Shenzhen, China, 2020. Emerg Infect Dis. 2020; 26(6): 1320–1323. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurke RM, Midgley CM, Dratch A, et al.: Active monitoring of persons exposed to patients with confirmed COVID-19 — United States, January–February 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(9): 245–246. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPan X, Chen D, Xia Y, et al.: Asymptomatic cases in a family cluster with SARS-CoV-2 infection. Lancet Infect Dis. 2020; 20(4): 410–411. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuo Y, Qin W, Wang Z, et al.: Factors influencing social distancing to prevent the community spread of COVID-19 among Chinese adults. Prev Med. 2021 February; 143: 106385. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTull MT, Edmonds KA, Scamaldo KM, et al.: Psychological outcomes associated with stay-at-home orders and the perceived impact of COVID-19 on daily life. Psychiatry Res. 2020; 289: 113098. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCohen DB, Luck M, Hormozaki A, et al.: Increased meaningful activity while social distancing dampens affectivity; mere busyness heightens it: Implications for well-being during COVID-19. PLOS ONE. 2020; 15(12): e0244631. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBernstein R: 7 Cultural Differences in Nonverbal Communication. Point Park University Online. https://online.pointpark.edu/business/cultural-differences-in-nonverbal-communication/\n\nUK Essays. The Communication Style In Middle East Cultural Studies Essay [Internet]. November 2018. [Accessed 22 February 2021]. https://www.ukessays.com/essays/cultural-studies/the-communication-style-in-middle-east-cultural-studies-essay.php?vref=1\n\nPăun C: The rationality of a social animal. Manag Dyn Knowl Econ. 2016; 4(1): 125–140.\n\nMiller KJ, Shenhav A, Ludvig EA: Habits without values. Psychol Rev. 2019 March; 126(2): 292–311. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDi Renzo L, Gualtieri P, Pivari F, et al.: Eating habits and lifestyle changes during COVID-19 lockdown: an Italian survey. J Transl Med. 2020; 18(1): 1.e5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPellegrino G, Beigi DM, Angelelli C, et al.: COVID-19 and systemic sclerosis: Analysis of lifestyle changes during the SARS-CoV-2 pandemic in an Italian single-center cohort. Clin Rheumatol. 2021; 40(4): 1393–7s. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumari A, Ranjan P, Vikram NK, et al.: A short questionnaire to assess changes in lifestyle-related behaviour during COVID 19 pandemic. Diabetes Metab Syndr. 2020; 14(6): 1697–1701. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHao F, Xiao Q, Chon K: COVID-19 and China’s hotel industry: Impacts, a disaster management framework, and post-pandemic agenda. Int J Hosp Manag. 2020; 90: 102636. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorawska L, Cao J: Airborne transmission of SARS-CoV-2: The world should face the reality. Environ Int. 2020; 139: 105730. PubMed Abstract | Publisher Full Text | Free Full Text\n\nO’Neill LAJ, Netea MG: BCG-induced trained immunity: Can it offer protection against COVID-19? Nat Rev Immunol. 2020; 20(6): 335–337. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBatty M: The coronavirus crisis: What will the post-pandemic city look like? Urban Analytics and city Science. 2020; 47(4): 547–552. Publisher Full Text\n\nJayaweera M, Perera H, Gunawardana B, et al.: Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ Res. 2020; 188: 109819. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQadir S: Post-Pandemic era: will physical distancing be a perceived way of lifestyle? Harvard Dataverse, V3, UNF:6:f6Si7sRUDesaBrgphOw+3g== [fileUNF]. 2021. Publisher Full Text"
}
|
[
{
"id": "98081",
"date": "17 Nov 2021",
"name": "Sana Mangrio",
"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\nIs the work clearly and accurately presented and does it cite the current literature?\nThe article overall is written well, using appropriate study design and cites current literature, but some changes are required regarding methodology and conclusion.\n\nAre sufficient details of methods and analysis provided to allow replication by others?\nThe sample size details are not mentioned in detail, how the sample 1066 was obtained, which prevalence was used in the Raosoft. What was the total population from which the representative sample was taken?\n\nSimple random sampling technique and sampling frame not mentioned in detail about how the technique was employed.\n\nThe data collection does not align with the sampling technique. The sampling technique mentioned is Simple Random but data collection procedure states that a link was sent to WhatsApp contacts of the authors, which implies it is a convenient sampling method.\n\nAre the conclusions drawn adequately supported by the results?\nThe conclusion in the abstract states that since 1/3 of participants planned to continue physical distance, it indicates that life will not be the same after the pandemic. The 1/3 result mentioned here is not the correct ratio to draw such conclusions.\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? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7585",
"date": "13 Jan 2022",
"name": "soban khan",
"role": "Author Response",
"response": "Comment 1: The sample size details are not mentioned in detail, how the sample 1066 was obtained, which prevalence was used in the Raosoft. What was the total population from which the representative sample was taken? Reply: It was not a prevalence study (like caries, diabetes, heart disease, etc) hence prevalence could not be obtained from literature. This study was conducted on general population and none of the specific group of the population was targeted hence for these kinds of scenarios 50% is generally used (which was used and mentioned). Secondly, regarding the total population of the Eastern region, we have added the text and reference in the method section. Comment 2: Simple random sampling technique and sampling frame not mentioned in detail about how the technique was employed. Reply: Revised and sample frame is mentioned now in the revised version Comment 3: The data collection does not align with the sampling technique. The sampling technique mentioned is Simple Random but data collection procedure states that a link was sent to WhatsApp contacts of the authors, which implies it is a convenient sampling method. Reply: Some revisions have been made in the respective parts. Comment 4: The conclusion in the abstract states that since 1/3 of participants planned to continue physical distance, it indicates that life will not be the same after the pandemic. The 1/3 result mentioned here is not the correct ratio to draw such conclusions. Reply: Revised in the new version."
}
]
},
{
"id": "99540",
"date": "09 Dec 2021",
"name": "Dr. Shamta Sufia",
"expertise": [
"Reviewer Expertise dental public health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe concept of identifying the opinions of people regarding physical distancing post-pandemic is interesting. However, for example in the Introduction some changes in the sequence of ideas can improve the flow e.g. the guidelines for avoiding infections (paragraph 3) can be presented before the effectiveness of social distancing can be addressed (paragraph 2) only after this taking up of recurrent waves of Covid infection seems logical. The transition to non verbal communication is quite abrupt and need reconsideration.\nMethods\nOn how many subjects was the questionnaire pilot tested and where was the questionnaire pilot tested?\n\nWere any changes made to the questionnaire?\n\nDid the sample cover responses from all sections of the society since personal contacts were used through social media.\nResults\nFor a non native English speaker the narrative becomes a little confusing as to what is meant by agreement/dis-agreement to the statements. A simple explanation for the reader would be more appropriate.\nDiscussion\nUsing simple terms as individuals feeling of sense of security or otherwise would make reading less confusing.\n\nDiscussing the limitation of the study the authors need to state the large sample size as a strength of the study, However, limiting it to one geographical region is a limitation. They also fail to identify religious factors that could have acted unfavorably on the study.\n\nSome of the closing statements in the discussion are repetitive and hence can be rephrased.\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": "7586",
"date": "13 Jan 2022",
"name": "soban khan",
"role": "Author Response",
"response": "Comment 1: The concept of identifying the opinions of people regarding physical distancing post-pandemic is interesting. However, for example in the Introduction some changes in the sequence of ideas can improve the flow e.g. the guidelines for avoiding infections (paragraph 3) can be presented before the effectiveness of social distancing can be addressed (paragraph 2) only after this taking up of recurrent waves of Covid infection seems logical. The transition to non verbal communication is quite abrupt and need reconsideration. Reply: Revised as suggested. Comment 2: On how many subjects was the questionnaire pilot tested and where was the questionnaire pilot tested? Reply: Revised and added in third para of method section. Comment 3: Were any changes made to the questionnaire? Reply: Not required because of having acceptable value kappa statistics. Comment 4: Did the sample cover responses from all sections of the society since personal contacts were used through social media. Reply: Added in the study limitations in the revised version. Comment 5: For a non native English speaker the narrative becomes a little confusing as to what is meant by agreement/dis-agreement to the statements. A simple explanation for the reader would be more appropriate. Reply: It is mentioned in the method that original questionnaire had 5-point Likert scale (1 = “Never,” 2 = “Seldom,” 3 = “Sometimes,” 4 = “Frequently,” 5 = “Always”). For the simplicity of the analysis and results presentation we merged them into 3 categories which was also mentioned in the fourth para of method section. Comment 6: Using simple terms as individuals feeling of sense of security or otherwise would make reading less confusing. Reply: Discussion has been revised. Comment 7: Discussing the limitation of the study the authors need to state the large sample size as a strength of the study, However, limiting it to one geographical region is a limitation. They also fail to identify religious factors that could have acted unfavorably on the study. Reply: Study limitations has been revised. Comment 8: Some of the closing statements in the discussion are repetitive and hence can be rephrased. Reply: Conclusion has been revised."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1090
|
https://f1000research.com/articles/10-915/v1
|
13 Sep 21
|
{
"type": "Case Report",
"title": "Case Report: Digital analysis of occlusion with T-Scan Novus in occlusal splint treatment for a patient with bruxism",
"authors": [
"Dobromira Shopova",
"Tanya Bozhkova",
"Svetlana Yordanova",
"Miroslava Yordanova",
"Tanya Bozhkova",
"Svetlana Yordanova",
"Miroslava Yordanova"
],
"abstract": "Bruxism is a disease with a multifactorial etiology. Its clinical manifestations are most often an unaesthetic smile with abraded tooth surfaces, temporomandibular disorders and muscle hyperactivity. Here we present a case of bruxism where proper articulation of the occlusal splint was performed using the T-scan Novus system. A patient with bruxism underwent treatment with stabilization splint made by 3D printer technology. Intraoral scanning was performed using Trios Color (3Shape, 2014), and the digital design was achieved using the 3Shape Dental system design - splint studio. Formlabs Form 2 printer with biocompatible resin Dental LT Clear Resin was used for printing. The T-Scan Novus system with software attached to it, version 9.1, was used for digital examination of the occlusion. A 2.7 mm thick occlusal splint was developed, and the software adapted the occlusion with antagonists. After adjustment with T-Scan Novus, a reduction in disocclusion time of the patient was achieved, which is a desired result in the treatment of bruxism. The position of the joint components was proven radiologically. The treatment of bruxism with splint therapy continues to be the main method of treatment. Using digital technology allows for more accurate constructions and precise balancing of occlusal relationships.",
"keywords": [
"T-Scan Novus",
"digital splint design",
"3Shape",
"bruxism"
],
"content": "Introduction\n\nBruxism is a disease with a multifactorial etiology, such as stress, occlusal factors and trauma. Its clinical symptoms are most often abraded tooth surfaces, muscle hyperactivity, temporomandibular joint (TMJ) disorders (pain, clicking, limited opening), and in advanced cases headache and hearing problems can be observed.1\n\nThe treatment of bruxism is reduced to several main methods - increasing the vertical dimension of occlusion (VDO) to normal, medialization of the mandible to influence the position of the joint condyle in the joint fossa and release the disc, and positioning the mandible in a balanced stable occlusion.2,3 This is achieved by splint therapy for a certain adaptation period and then the result can be fixed by orthodontic treatment, adhesive restorations or prosthetic construction.4 The stabilization splint is indicated for the most common symptoms of TMJ and muscle.2\n\nDigital technologies for dental purposes have undergone enormous development in recent years. Brand giants have developed laboratory protocols from the initial unit of digital model creation (via intraoral or laboratory scanner), through to the modeling of substructures (via design software) to the actual creation of the final product (using 3D printing and CAD/CAM methods). Modern dentistry is strongly influenced by digital technologies.5-7 Innovative technologies already have an established protocol for creating splints with personal design, from different materials and by different methods.8-10\n\nAchieving a balanced occlusion requires a number of evenly distributed contacts.11 Articulation paper is widely used in practice when registering occlusal contacts. The interpretation of the markers obtained with articulation paper hides the possibility of making mistakes, as it is subjective. It is wrong to perceive large and dark markers as the places with the highest load.12 With articulation paper, it is only possible to locate the contacts. The T-Scan Novus digital occlusion analysis system is used to study the sequence of occurrence and the strength of the occlusal contacts. Created 35 years ago by the Maness, this system has proven its usefulness in the study of occlusal contacts. When using T-Scan, obtained information allows accurate occlusal adjustment. The registered contacts are displayed as 2D and 3D images, and are colored in different colors depending on the applied force. The system automatically calculates occlusion time (OT) and disocussion time (DT). The OT is the elapsed time in seconds, measured from the first tooth contact until the last tooth contact. Maximum intercuspation always occurs before the patient achieves maximum bite force. The OT describes the degree of bilateral time simultaneity present in a patient occlusion. The ideal duration of OT is ≤0.2 s. The DT is the elapsed time in seconds, measured from the beginning of an excursive movement made in any direction (left, right, or forward) with all teeth in maximum intercuspation until only canines and/or incisors are in contact. The ideal duration of DT is ≤0.5 s.13 Kerstein and Wright14 were the first to suggest that some patients with temporomandibular disorders, including those with bruxism, can be treated by reducing DT. They correct DT using a technique they call immediate complete anterior guidance development (ICAGD). This approach to occlusal therapy establishes immediate posterior disocclusion in all mandibular movements, prior to any habitual closure adjustments.15 Patients with myofascial pain have been shown to have increased DT. By the decreasing of DT, it reduces the hyperactivity of masseter and temporalis, the main muscles closing the lower jaw.15,16\n\nHere, we report a patient with bruxism, where proper articulation of the occlusal splint was performed using the T-scan Novus System.\n\n\nCase report\n\nA 56-year-old female patient, Bulgarian shop assistant, underwent treatment for bruxism. The leading complaints were an unaesthetic appearance of the smile, muscle fatigue almost all day and the clicking of both TMJ. Intraoral examination revealed highly abraded tooth surfaces entering the dentin area and a flattened smile line (Figures 1 and 2). The main masticatory muscles, masseter and temporalis, had increased tone, and the patient reported headaches related to this. On palpation of the TMJ, the patient responded with mild to moderate pain. There was a sharp click as the jaw was opened wide.\n\nWe decided to treat the patient with 3D printed stabilization splints. For this purpose, a digital work protocol was applied. An intraoral scan was performed with a Trios Color scanner (3Shape). The splint protocol requires imaging of the upper, lower jaw, left and right bite. The 3Shape Dental system design - splint studio was used for digital design. The splint was made using 3D printing with a Formlabs Form 2 printer and biocompatible resin (Dental LT Clear Resin).\n\nThe T-Scan Novus system with software attached to it, version 9.1, was used for digital examination of the occlusion. For the intraoral localization of the contacts, a two-stage technique was applied using Bausch 40 microns articulation paper and Bausch 12 microns articulation foil.\n\nThe digital software allows different design options. In this case, the following parameters of the lower jaw position were set: vestibular thickness of the splint at 1 mm; occlusal opening at 2.7 mm; and protrusion at 1 mm (Figure 3).\n\nWhen designing the occlusal surfaces, an option with relief to the antagonists was set. A surface modeled in this way has a slight occlusal relief, which leads the opposite jaw to the designed position. Occlusal surfaces were software-extended and provide wider contact. This is especially evident in the frontal teeth area. In this way a balanced stable occlusion was achieved. As the patient's clinical crowns were without retention areas, the splint borders were located to the cervical zone vestibularly and palatally, except the distal teeth, where the borders were 1 mm up of the cervix vestibularly. This extension also contributed to its stable position (Figures 4 and 5).\n\nOnce the splint had been designed, its adaptation to the tooth surfaces was checked by a silicone test (Figures 6 and 7).\n\nAfter proving its stable position on the tooth surfaces, we proceeded to computer-guided occlusal splint adjustment with the T-Scan Novus System.\n\nFirstly, we registered occlusal contacts with the splint in the mouth using the T-Scan Novus software. Registered occlusal contacts are represented as two-dimensional contour images or three-dimensional images. The strength of the contacts is determined in color by the help of a scale; weak contacts are colored in blue and strong contacts in red (Figure 8). In our patient, uneven distribution of occlusal contacts with predominance of forces in the left side was established. In addition, center of force (COF) was shifted to the left. Elevated values of OT (0.52 s) and DT (0.74 s) were reported.\n\nVisualization of the occlusal contacts was done intraorally with articulation paper and foil. After removing the strong contacts, a new record was made (Figure 9). This revealed that a greater load was still received by the left side, but the forces were reduced. The COF was still shifted to the left, at the periphery. Reduced OT values (0.47 s) were detected and DT values (0.4 s) were normalized.\n\nOn the last recording of the occlusion, evenly distributed contacts in the area of the lateral teeth were established. The forces on both sides are approximately equal (right side 50.3%, left side 49.7%) and COF was in the middle. The values of OT and DT were normal (0.27 s and 0.4 s, respectively) (Figure 10).\n\nThe occlusion of the patient visualized by a two-stage technique (Bausch 40 microns articulation paper and Bausch 12 microns articulation foil) almost confirmed the result of the digitally obtained result. The frontal area was marked with contacts with the articulation paper and foil, which weren’t registered by the T-Scan Novus System (Figure 11).\n\nA radiological examination was performed to check the condition of the TMJ. Four positions of the joint were made: in open and closed position, with the splint, and with the splint and a 1.5 mm spacer (Figures 12 and 13).\n\nThe radiological exam shows that there was symmetry between the right and left TMJ, no structural changes of the articular condyle and eminence were detected, the joint condyle was located symmetrically in the joint capsule, and when the mouth was opened, the condyle passes the eminence, the so-called habitual luxation.\n\n\nDiscussion\n\nThe treatment of bruxism is difficult and long. Visual evidence is needed that a treatment plan is working. T-Scan Novus visualizes the contacts between the jaws, the movement of the lower jaw, as well as establishes values of parameters (OT and DT), which are of major importance for the treatment of bruxism.\n\nStabilization splints for patients with bruxism aim to raise TMJ pain, muscle hyperactivity and restore VDO.2,3 Extending occlusal surfaces contributes to a more stable positioning of the lower jaw. The lack of blocks and preliminary contacts favors the final result of the treatment.2,4\n\nDigital design enables a very good and even adaptation of the splint to the tooth surfaces to be achieved. Occlusal surface was less precise. The reason can be found in the minimum output thickness of the material to be made (for 3D printing), which the software automatically sets. When using a splint milling by CAD/CAM technology, the mismatch can be sought again in the minimum thickness of the material, but also the limitation of the thinnest bur for cutting.6-8\n\nThe T-Scan Novus System shows more than just occlusal contacts. In the case of bruxism, it is more valuable to rely on OT and DT. In our study, during the clinical adjustment, a reduction of the values was achieved by almost half; the reported OT and DT approached the norm (OT: 0.27 s, norm ≤0.2 s; DT: 0.4 s, norm ≤0.5 s). The achieved result (DT) is a proven method of treatment for bruxism.14,15\n\nIn our study, visualization of the registered intraoral occlusal contacts was performed by a two-stage technique with articulation paper 40 microns and articulation foil 12 microns. When comparing the obtained results with those of the T-Scan Novus system, differences in the number and location of the occlusal contacts were established. This proves the possibility of registering false positive contacts when using articulation paper.12\n\nRadiological examination is the only option for objective examination of TMJ. As an initial study it serves to analyze the anatomical structures, their location relative to each other, and to exclude other causes of joint pain (trauma, ankylosis, tumor disease). X-rays taken after splinting prove the position of the joint components. In case of unsatisfactory or irrelevant placement, the splint should be redesigned.1,4\n\n\nConclusion\n\nThe main method of bruxism treatment continues to be splint therapy. Its combination with digital technologies allows more precise constructions and more detailed visualizations at each stage - design and dental adaptation of the splint, occlusal relief and occlusal relationships. As shown in our patient, with the T-Scan Novus system, it is possible to achieve optimal, harmonious occlusal ratios.\n\n\nConsent\n\nWritten informed consent was obtained from the patient for the publication of the case report with any associated images.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgements\n\nIntraoral scanning and splint design were made at the CAD/CAM Center Dental Medicine at the Research Institute, Medical University - Plovdiv, Bulgaria.\n\n\nReferences\n\nOkeson JP: Management of Temporomandibular Disorders and Occlusion-E-Book. Elsevier Health Sciences. 2019.\n\nAl-Ani M, Ziad, et al.: Stabilisation splint therapy for temporomandibular pain dysfunction syndrome. Cochrane Database of Systematic Reviews . 2004; 1. PubMed Abstract | Publisher Full Text\n\nLakshmi MS, et al.: Occlusal Splint Therapy in Temporomandibular Joint Disorders: An Update Review. J International Oral Health . 2016; 8(5). Publisher Full Text | Free Full Text\n\nBumann A, Lotzmann U: TMJ Disorders and Orofacial Pain . Stuttgart, New York: Thieme; 2002.\n\nDawood A, Marti BM, Sauret-Jackson V, et al.: 3D printing in dentistry. Br Dental J. 2015; 219(11): 521–529. Publisher Full Text\n\nMikolajczyk T, Malinowski T, Moldovan L, et al.: CAD CAM system for manufacturing innovative hybrid design using 3D printing. Procedia Manufacturing. 2019; 32: 22–28. Publisher Full Text\n\nZhou Q, Wang Z, Chen J, et al.: Development and evaluation of a digital dental modeling method based on grating projection and reverse engineering software. J Prosthetic Dentistry. 2016; 115(1): 42–46. Publisher Full Text\n\nEdelhoff D, et al.: CAD/CAM splints for the functional and esthetic evaluation of newly defined occlusal dimensions. Quintessence Int. 2017; 48.3.\n\nNota A, Ryakhovsky AN, Bosco F, et al.: A Full Digital Workflow to Design and Mill a Splint for a Patient with Temporomandibular Joint Disorder. Appl. Sci. 2021; 11(1): 372. Publisher Full Text\n\nVenezia P, Muzio LL, De Furia C, et al.: Digital manufacturing of occlusal splint: From intraoral scanning to 3D printing. J Osseointegration. 2019; 11(4): 535–539. Publisher Full Text\n\nAtashrazm P, Lari HA, Khorsand M: An Evaluation of Occlusal Contacts of Remounted Complete Denture before Final Occlusal Adjustment. J Dentistry. Shiraz University of Medical Sciences. 2009; 9: 1–5.\n\nCarey J, Craig M, Kerstein RB, et al.: Determining a relationship between applied occlusal load and articulation paper mark area. Open Dent J. 2007; 1: 1–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKerstein R: Handbook of research on computerized occlusal analysis technology applications in dental medicine. IGI global. 2014: 1–15.\n\nKerstein RB, Wright NR: Electromyographic and computer analyses of patients suffering from chronic myofascial paindysfunction syndrome: before and after treatment with immediate complete anterior guidance development. J Prosthet Dent. 1991; 66: 677–686. PubMed Abstract | Publisher Full Text\n\nKerstein RB: Disocclusion time-reduction therapy with immediate complete anterior guidance development to treat chronic myofascial pain-dysfunction syndrome. Quintessence Int. 1992; 23: 735–747. PubMed Abstract\n\nKerstein RB, Lowe M, Harty M, et al.: A force reproduction analysis of two recording sensors of a computerized occlusal analysis system. Cranio. 2006; 24: 15–24. PubMed Abstract | Publisher Full Text\n\nKerstein RB: Reducing chronic masseter and temporalis muscular hyperactivity with computer-guided occlusal adjustments. Compend Contin Educ Dent. 2010; 31: 530–534. 536538. PubMed Abstract"
}
|
[
{
"id": "95636",
"date": "21 Oct 2021",
"name": "Bozhidar Yordanov",
"expertise": [
"Reviewer Expertise Prosthetic Dental Medicine and Dental Implantology"
],
"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 currentness of the subject discussed in this paper is determined by the contemporary requirements for optimum rehabilitation of the masticatory system in patients with bruxism. Splint therapy of bruxism is still the basic method of treatment to relieve specific clinical symptoms - temporomandibular disorders, muscle hyperactivity, and lost esthetics as a result of abrasion of tooth occlusal surfaces. Contemporary digital methods for the examination of occlusion and fabrication of occlusal splints contribute to the precision and better final results following occlusal therapy. Patient examination, treatment planning, digital process for fabrication of the splint, adjustment of occlusal contacts using conventional and modern methods and technologies, discussion of the results and conclusions are sufficient enough for understanding diagnosis, planning, treatment of bruxism and to be useful for dental practitioners.\nCritical notes:\nThe background of the case’s history and progression is not completely described in sufficient detail.\n\nThe scientific value of this paper will be increased by replacing some specific terms with more accurate ones: occlusal splint instead of stabilization splint; dental medicine instead of dentistry; bilaterally balanced occlusion instead of balanced occlusion; adjustment of occlusal contacts instead of articulation; retail worker instead of shop assistant; opposing teeth instead of antagonists; anterior instead of frontal; occlusal interferences instead of blocks.\n\nIn the second section of the Discussion, probably there is a mistake: \"Stabilization splints for patients with bruxism aim to RAISE TMJ pain, muscle hyperactivity...\". Splints are used to relieve pain, not to raise it.\nThe critical notes above do not decrease the scientific and practical value of the presented article.\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? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "7532",
"date": "13 Jan 2022",
"name": "dobromira shopova",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your advices! I will correct them in the final version of the article!"
}
]
},
{
"id": "99206",
"date": "18 Nov 2021",
"name": "Dinesh Rokaya",
"expertise": [
"Reviewer Expertise Clinical dentistry",
"prosthetic dentistry",
"digital dentistry",
"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 article presents the management of bruxism with occlusal splint with adjustment done using the T-scan Novus system.\nAbstract:\nPlease mention which Trios was used, 3 or 4.\nIntroduction:\nAt present, although various scanners are available in the market, the Trios system presents the best scan which system is used in this case study.\n\nThe authors need to add the following current literature in the introduction:\nAmornvit et al., 20211 - This study compared the various intraoral scanners and the results show that Trios showed the best results.\n\nAmornvit et al., 20202 - This study explained the confocal technique used in Trios which showed high accuracy especially in the posterior region.\n\nCase Report:\nIt is better to add details of the product and software such as Trios, resin, etc. Product name, Company, City, and Country.\n\nFigures 12 and 13: Each X-ray needs to be labeled.\n\nHow often the recall was done and how long the splint was given needs to be mentioned.\nDiscussion:\nAt present, scanning the upper arch, lower arch and bite allows to check the occlusion and force on the area of each tooth using 3Shape Dental System. This is also shown in this case. The occlusion can also be done more precisely using T-Scan but the disadvantage is this will add extra cost to the dentist and the patient. Hence, the authors need to add the specific use of T-Scan in this case study.\n\nIn addition, the authors can discuss the indications and limitations of each system in checking the occlusion. This comparison can be done using a table. The following articles can be helpful: Lee et al., 20183; Cheng et al., 20184; Solaberrieta et al., 20165.\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? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "7531",
"date": "13 Jan 2022",
"name": "dobromira shopova",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your advices! I will answer point by point: Abstract: Please mention which Trios was used, 3 or 4. Author response: The previous generation intraoral scanner of 3Shape Trios color, from 2014, was used. Introduction: At present, although various scanners are available in the market, the Trios system presents the best scan which system is used in this case study. The authors need to add the following current literature in the introduction: Amornvit et al., 20211 - This study compared the various intraoral scanners and the results show that Trios showed the best results. Amornvit et al., 20202 - This study explained the confocal technique used in Trios which showed high accuracy especially in the posterior region. Author response: I added them, thank you! Case Report: It is better to add details of the product and software such as Trios, resin, etc. Product name, Company, City, and Country. Author response: The information is added! Figures 12 and 13: Each X-ray needs to be labeled. Author response: I labeled them, thank you! How often the recall was done and how long the splint was given needs to be mentioned. Author response: After 3 months the recall was made. Clinical symptoms were reduced. The control study with T-Scan showed small changes, but within the same limits of OT and DT as the placement. Discussion: At present, scanning the upper arch, lower arch and bite allows to check the occlusion and force on the area of each tooth using 3Shape Dental System. This is also shown in this case. The occlusion can also be done more precisely using T-Scan but the disadvantage is this will add extra cost to the dentist and the patient. Hence, the authors need to add the specific use of T-Scan in this case study. Author response: Our study with the T-Scan system revealed an unbalanced distribution of occlusal contacts, although they were designed to be balanced by 3Shape Splint studio software. The reason can be found in the minimum output thickness of the material to be made (for 3D printing), and which the software automatically sets. There is evidence in the literature that one of the limitations of intraoral scanners is that they cannot measure the intensity of occlusal forces. The T-Scan system has been shown to be a reliable method for assessing the occlusal contact zone (Ayuso‐Montero, R., Mariano‐Hernandez, Y., Khoury‐Ribas, L., Rovira‐Lastra, B., Willaert, E., & Martinez‐Gomis, J. (2020). Reliability and validity of T‐scan and 3d intraoral scanning for measuring the occlusal contact area. Journal of Prosthodontics, 29(1), 19-25). In addition, the authors can discuss the indications and limitations of each system in checking the occlusion. This comparison can be done using a table. The following articles can be helpful: Lee et al., 20183; Cheng et al., 20184; Solaberrieta et al., 20165. Author response: The use of the T-Scan system provides data for more in-depth occlusal analysis. Through this study, it is possible to determine whether the occlusion is balanced and also the sequence, strength, and location of the occlusal contacts. 3Shape software does not have these features. Our opinion on the benefits of using the computerized analysis system is confirmed by other authors (Kerstein RB. Current applications of computerized occlusal analysis in dental medicine. Gen Dent. 2001; 49: 521-530; Buduru S, Mesaros A, Talmaceanu D., Baru O, Ghiurca R, Cosgarea R. Occlusion in the digital era: a report on 3 cases. Medicine and pharmacy reports. 2019; 92 (3): 78). Therefore, we recommend that, if technically possible, you should not rely solely on the information provided by the intraoral scanner, however accurate it may be."
}
]
}
] | 1
|
https://f1000research.com/articles/10-915
|
https://f1000research.com/articles/11-38/v1
|
13 Jan 22
|
{
"type": "Method Article",
"title": "Improving prediction of core transcription factors for cell reprogramming and transdifferentiation",
"authors": [
"Mikhail Raevskiy",
"Anna Kondrashina",
"Yulia Medvedeva",
"Anna Kondrashina"
],
"abstract": "Identification of transcription factors (TFs) that could induce and direct cell conversion remains a challenge. Though several hundreds of TFs are usually transcribed in each cell type, the identity of a cell is controlled and can be achieved through the ectopic overexpression of only a small subset of so-called core TFs. Currently, the experimental identification of the core TFs for a broad spectrum of cell types remains challenging. Computational solutions to this problem would provide a better understanding of the mechanisms controlling cell identity during natural embryonic or malignant development, as well as give a foundation for cell-based therapy. Herein, we propose a computational approach based on over-enrichment of transcription factors binding sites (TFBS) in differentially accessible chromatin regions that could identify the potential core TFs for a variety of primary human cells involved in hematopoiesis. Our approach enables the integration of both transcriptomic (single-cell RNA sequencing, scRNA-seq) and epigenenomic (single-cell assay for transposable-accessible chromatin, scATAC-seq) data at the single-cell resolution to search for core TFs, and can be scalable to predict subsets of core TFs and their role in a given conversion between cells.",
"keywords": [
"cell conversion",
"scRNA-seq",
"scATAC-seq",
"transcription factors",
"epigenetics"
],
"content": "Introduction\n\nThe cell identity is largely controlled by transcription factors (TFs). TFs regulate gene expression by binding DNA in a sequence-specific manner, targeting short sequences called transcription factor binding sites (TFBS). Although almost half of all TFs are expressed in a particular cell type,21 only a minor share of these TFs — so-called core TFs — are sufficient to maintain cell identity by defining the corresponding gene expression programs.11,22,23 The identification of core TFs for a large number of cell types would be a valuable addition for an atlas of transcription regulators supplementing the Encyclopedia of Regulatory DNA Elements (ENCODE, Ref. 16). Such an atlas, in turn, would facilitate systematic investigation of regulatory networks and contribute to establishing and refining direct cell conversion protocols for clinically relevant cell types.6,7\n\nSystematic determination of core TFs controlling individual cell type identity has previously been attempted. Initial efforts were mainly focused on the experimental screening of the TFs, presumably regulating the deferentially expressed genes (DEGs) in the comparison between query cell type, and a small number of alternative cell types that could potentially serve as an initial stage for conversion. Some of these TFs could play a role as regulators controlling cellular identities. For example, studies showed that over-expression of MyoD1 in fibroblasts leads to its conversion into the muscle cells,19 while inhibition of Oct4 resulted in the suppression of the pluripotent stem cell population during mammalian embryo development.12 Recent experiments with TF over-expression leading to conversion of cells to another cell type appeared to be used as a stringent test of the potential of specific TFs to establish and maintain cell identity.11,22,23 Nonetheless, while being illustrative validation for each TF, such experiments are still time- and labor-consuming, and resulting observations are limited to specific cell types.\n\nThe growth of genome-wide sequencing technologies allowed to develop computational systems capable of predicting candidate core TFs.2,9,14,17 However, being broad in scope and easily scalable, these methods infer predictions using preferably only bulk RNA sequencing (RNA-seq) data, which estimates the average gene expression level across a hundred thousands to millions of cells. As a result, they are insufficient for analysis of heterogeneous systems, such as early embryonic populations or complex tissues, including brain or bone marrow.\n\nHere we propose an approach that uses single-cell expression and DNA accessibility data to select core TFs for cell differentiation or directed conversion. A distinct feature of the approach is incorporating not only TFs expression levels in the original and target cell types, but also (1) the chromatin conditions in gene regulatory elements, as well as (2) TF putative binding sites. Thus, this method simultaneously takes into account the accessibility and expression profile of the initial and terminal cell types involved in the conversion. Additionally, our method uses modified gene set enrichment analysis (GSEA)18 for the selection of core TFs, thus reducing the number of arbitrary thresholds in the pipeline.\n\n\nResults\n\nTo validate our method, we applied it to hematopoietic differentiation datasets,5,1 since this process has been extensively studied. We provided TFs for the hematopoietic stem cells (HSC) differentiation into CD4(+) cells as an example (Table 1). The detected TFs are critical for the HSC-to-CD4(+) cells differentiation. The top-ranked TF, TCF7, is a transcription activator recruited in T-cell lymphocyte differentiation and is necessary for the survival of immature CD4(+) and CD8(+) thymocytes.13,10 RORA gene plays a crucial role in the regulation of embryonic development, differentiation and immunity.4 TBX21 is a lineage-defining TF, which initiates Th1(CD4(+)) lineage development from naive T helper (CD4(+)) precursor cells.24,10 The LEF1 TF has a higher affinity to a functionally important site in the T-cell receptor-alpha enhancer, and thereby its presence in these regions increases the activity of the enhancer.3\n\n\nMethods\n\nThe proposed approach (Figure 1) consists of the following steps. First, for two given cell types involved in cell differentiation or conversion pathways, the minimal spanning tree (MST) is reconstructed based on the open chromatin in regulatory regions (Figure 2, Figure 3). Then, a differential accessibility analysis (DAA) between initial and final cell types is performed to retrieve a list of genomic regions (ATAC-seq peaks) ranked by the statistical significance of a change in chromatin accessibility for a given cell conversion (Figures 4, 5). Next, the sequences corresponding to each of the ranked regions undergo the functional annotation with TFBS. Finally, TFs ranking is inferred by GSEA,18 which was adjusted to estimate the tendency of TFBS for given TF under investigation to be over-represented at the most statistically significant genomic regions for a given cell differentiation or conversion.\n\nHSC, hematopoietic stem cells; MPP, multipotentent progenitor; LMPP, lymphoid-primed multipotent progenitor; CLP, common lymphoid progenitor; NK, natural killer cells.\n\nscATAC-seq data (GEO: (GSE96769, GSE111586)) were used to reconstruct the minimal spanning tree (MST) of hematopoietic cell types, the hierarchy of which was aligned along pseudo-time, reflecting a degree of pluripotency of the cells observed in the single-cell assay for transposable-accessible chromatin (scATAC-seq) dataset.15 Thus, the obtained MST presents a collection of possible cell trajectories among the analyzed cell types.\n\nSimilarly to DEG analysis,20 a differential accessibility analysis (DAA) of genomic regions was performed between two given cell types on the cell trajectory by hrefhttps://www.bioconductor.org/packages/devel/bioc/manuals/slingshot/man/slingshot.pdfSlingshot v2.3. Accordingly, for each cell population on the MST, such a subset of regions ranked by p-value can be obtained, discriminating given cell population from others.\n\nWe excluded from the downstream analysis TFs that had either a near-zero median expression (below 5% percentile) in the final cell type or had a higher expression in the original cell types based on scRNA-seq data (GEO: GSE74912). Thus, only TFs uniquely expressed in a final cell population were considered.\n\nGenomic regions (scATAC-seq peaks from GSE74912) were listed and ranked based on the significance of DAA (p-value < 0.01) performed by Monocle2, and used for functional annotation by TFBS using position weight matrices (PWM, p-value < 0.0001) from the HOCOMOCO database.8\n\nGSEA18 was modified to perform the TF ranking according to their significance for a given cell conversion.\n\nSince TF sequence preferences and, therefore, the quantity of TFBS for each TF is different, TFs annotations are presented highly unequally in the regions ranking. Thereby, GSEA here was utilized to infer the degree of TFBS abundance at the top of the regions ranking for a given conversion.\n\nConsequently, for GSEA, the genomic regions ranking annotated with TFBS was taken as a pre-ranked list of TFs and each separate factor as a signature gene set. The final TFs ranking obtained from GSEA, thus, represents the significance of distinct TFs for cell differentiation or conversion.\n\n\nDiscussion\n\nThe proposed pipeline utilizes both transcriptomic and epigenenomic data at the single-cell resolution to search for core TFs that enable cell differentiation and conversion within the human hematopoietic system. The transcription factors rankings obtained (Table 1) suggest that the current approach is capable of predicting subsets of core TFs as well as reflecting their importance for cell differentiation and conversion between cells.\n\n\nConclusions\n\nHerein, we described a method for integrating single-cell chromatin accessibility and gene expression data that can successfully select core TFs for cell differentiation and conversion in silico.\n\n\nData availability\n\nGene Expression Omnibus: A Single-Cell Atlas of in vivo Mammalian Chromatin Accessibility, https://identifiers.org/geo: GSE111586\n\nGene Expression Omnibus:Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation [scATAC-Seq], https://identifiers.org/geo: GSE96769\n\nGene Expression Omnibus: ATAC-seq data, https://identifiers.org/geo: GSE74912\n\nAnalysis code available from: https://github.com/annykay/transFactorsPrediction\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.5799254\n\nLicense: MIT\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe study was supported by Ministry of Science and Higher Education of the Russian Federation (agreement no. 075-15-2020-899).",
"appendix": "References\n\nBuenrostro JD, Corces MR, Lareau CA, et al.: Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation. Cell. 2018; 173(6): 1535–1548.e16. PubMed Abstract | Publisher Full Text\n\nCahan P, Li H, Morris SA, et al.: CellNet: Network biology applied to stem cell engineering. Cell. 2014; 158: 903–915. PubMed Abstract | Publisher Full Text\n\nChoi YS, Gullicksrud JA, Xing S, et al.: LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol. 2015; 16: 980–990. PubMed Abstract | Publisher Full Text\n\nCook DN, Kang HS, Jetten AM: Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism. Nuclear Receptor Research. 2015; 2. PubMed Abstract | Publisher Full Text\n\nCorces MR, Buenrostro JD, Wu B, et al.: Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 2016; 48: 1193–1203. PubMed Abstract | Publisher Full Text\n\nHenriques T, Gilchrist DA, Nechaev S, et al.: Stable pausing by rna polymerase II provides an opportunity to target and integrate regulatory signals. Mol. Cell. 2013; 52: 517–528. PubMed Abstract | Publisher Full Text\n\nIwafuchi-Doi M, Zaret KS: Pioneer transcription factors in cell reprogramming.2014.\n\nKulakovskiy IV, Vorontsov IE, Yevshin IS, et al.: HOCOMOCO: Towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis. Nucleic Acids Res. 2018; 46: D252–D259. PubMed Abstract | Publisher Full Text\n\nLang AH, Li H, Collins JJ, et al.: Epigenetic Landscapes Explain Partially Reprogrammed Cells and Identify Key Reprogramming Genes. PLoS Comput. Biol. 2014; 10: e1003734. PubMed Abstract | Publisher Full Text\n\nLuckheeram RV, Zhou R, Verma AD, et al.: CD4 +T cells: Differentiation and functions.2012.\n\nMorris SA, Daley GQ: A blueprint for engineering cell fate: Current technologies to reprogram cell identity.2013.\n\nNichols J, Zevnik B, Anastassiadis K, et al.: Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998; 95: 379–391. PubMed Abstract | Publisher Full Text\n\nNish SA, Zens KD, Kratchmarov R, et al.: CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J. Exp. Med. 2017; 214: 39–47. PubMed Abstract | Publisher Full Text\n\nRackham OJ, Firas J, Fang H, et al.: A predictive computational framework for direct reprogramming between human cell types. Nat. Genet. 2016; 48: 331–335. PubMed Abstract | Publisher Full Text\n\nReid JE, Wernisch L: Pseudotime estimation: Deconfounding single cell time series. Bioinformatics. 2016; 32: 2973–2980. PubMed Abstract | Publisher Full Text\n\nRivera CM, Ren B: Mapping human epigenomes.2013.\n\nRoost MS, Van Iperen L, Ariyurek Y, et al.: KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas. Stem Cell Reports. 2015; 4: 1112–1124. PubMed Abstract | Publisher Full Text\n\nSubramanian A, Tamayo P, Mootha VK, et al.: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 15545–15550. PubMed Abstract | Publisher Full Text\n\nTapscott SJ, Davis RL, Thayer MJ, et al.: MyoDL: a Myc Requiring Nuclear Phosphoprotein to Convert Region Homology Myoblasts Fibroblasts to. Adv. Sci. 2010.\n\nTarazona S: Differential Expression in RNA-Seq. Gene Expr. 2011.\n\nVaquerizas JM, Kummerfeld SK, Teichmann SA, et al.: A census of human transcription factors: Function, expression and evolution.2009.\n\nVierbuchen T, Wernig M: Molecular Roadblocks for Cellular Reprogramming.2012.\n\nYamanaka S: Induced pluripotent stem cells: Past, present, and future.2012.\n\nZhu J, Yamane H, Paul WE: Differentiation of Effector CD4 T Cell Populations. Annu. Rev. Immunol. 2010; 28: 445–489. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "119678",
"date": "27 Jan 2022",
"name": "Valentiva Boeva",
"expertise": [
"Reviewer Expertise Epigenetics",
"transcriptional control",
"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\nRationale:\nThe rationale of developing this method is clearly stated. The authors identify experimental work to be the bottleneck in identifying core transcription factors (TFs) and therefore suggest a computational approach to solve this challenge. However, the authors do not state if there are existing methods in the field that address this problem. This information should be included, also in case there are similar methods that are related to the problem of identifying core TFs.\nMethods:\nThe described methodology is overall understandable and seems technically sound. Nevertheless, parts of the described methods are too short and should be further specified. It includes\nDetails on the construction of the MST (what were exactly the input data? Some details on the algorithm or a reference would be useful too).\n\nMore details on how GSEA was adjusted in this method. What is the input into GSEA? Why is it applied?\n\nDetails on the parsing of the obtained TF rankings (e.g. if a threshold was used).\n\nNo information is given about data pre-processing requirements (scRNA-seq, scATAC-seq) to use the presented method. If the authors want their method to be used on other datasets this information should be included.\nData used in this study includes ‘A Single-Cell Atlas of in vivo Mammalian Chromatin Accessibility’ (GSE111586) which was obtained from mice. An explanation why this data was used should be included.\nReproducibility:\nThe analysis of this manuscript cannot be reproduced for a number of reasons. First, the code cannot be found from the link of the GitHub repository. (I assume that the correct link should be https://github.com/annykay/transFactorsPrediction- ) Second, major parts of the analysis are missing in the GitHub repository, as well as in the archived code repository. The missing parts include the construction of the MST, TF filtration and TFBS annotation and TF ranking via GSEA-like enrichment analysis and parsing of the obtained TF rankings.\nIn addition, there were a number of issues to reproduce the figures using the scripts that were available in the archived code repository.\nData referenced for Figure 3 (A) (GSE74912) do not correspond to scATAC-seq but to bulk ATAC-seq data.\n\nThe data referenced for Figure 3 (B) scRNA-seq are not retrievable from the accession number the authors specify. Another accession number was listed in the code (GSE74246) which seems to corresponds to bulk RNA-seq (not scRNA-seq) data.\n\nA random seed for the UMAP algorithm and other parameters should be specified in the scripts such that the results are reproducible.\n\nResults and discussion:\nThe main result of this study is a table of important TFs in hematopoietic cell differentiation. It is not clear why only these 5 TFs are reported (see comment on parsing of the obtained TF rankings). Moreover, the result is not clearly put into context in the discussion. Questions that have to be discussed include:\nAre the reported TFs all TFs involved in hematopoietic cell differentiation known from the literature?\n\nAre TFs involved in hematopoietic differentiation absent in the final enrichment list, if yes how many and what could be the reason that the method did not identify them?\n\nWere some core TFs newly discovered using this method?\n\nCan alternative methods, if they exist, retrieve these TFs?\n\nGiven the title, the authors claim that they can identify core TFs for cell reprograming. It is clear why the same idea could in principle be used in both cell reprograming and differentiation. However, the method is not applied to identify core TFs in cell reprograming in the manuscript. While the authors claim that their method can determine core TFs for cell differentiation this does not directly imply that the method can also be used to determine core TFs for cell reprogramming. If this result should be included in the title and the conclusion, results supporting this claim must be shown in the manuscript.\nOther comments:\nThere is a typo in referencing slingshot in paragraph Differential accessibility analysis.\n\nThe links to the Gene Expression Omnibus do not always work.\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? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "119675",
"date": "31 Jan 2022",
"name": "Erdem B. Dashinimaev",
"expertise": [
"Reviewer Expertise Cell biology",
"human cell reprogramming",
"regenerative biomedicine"
],
"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\nMajor comments:\nOn the whole, the article is unclear. I have no doubt that some thoughtful and valuable work has been done in which interesting data have been obtained, but in this manner, the entire work is presented incomprehensibly.\n\nThe abstract and introduction chapters are well written.\n\nThe Results chapter is poorly written and unclear, especially since the Methods chapter, which describes the proposed Pipeline, has moved behind the Results chapter. Considering that the main point of the article is the publication of the pipeline under development, perhaps it makes sense to eliminate the Methods chapter and move it to the Results chapter, taking into account the logic of the narrative. For example, the fact that the main result of the applied method was Table 1 becomes clear only at the end of the article from the Discussion chapter\n\nThe Discussion chapter was written extremely poorly. I suggest that this chapter should include references to similar published works (pipelines) from other teams in the field, and discuss their similarities and differences from your work (pipelines). It is also necessary to discuss the results in terms of the value of the data obtained, their potential applications in different fields of science and biotechnology. It is also necessary to highlight the disadvantages and limitations of your method and possible ways to solve them.\n\nMinor comments:\nFig.2. - missing the transcription of the abbreviations of cell type names.\n\nPerhaps, based on the logic of the narrative, swap Fig. 2 and Fig. 3.\n\nThe text contains a lot of abbreviations that are not explained in any way - for example TFBS, ATAC-seq, scATAC-seq, GSEA, DEG, Monocle2, PWM, HOCOMOCO, etc.\nOf course, for narrow specialists these acronyms make sense, but one of the tasks of scientific publications is to convey information to a wider audience in the most accessible way possible. All the more so given the multidisciplinary nature of F1000Research.\n\n\"Pluripotency\" is better replaced with \"stemness\". 1\n\nConclusion:\n\nI believe that the article requires significant revisions and rewrites.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\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? No\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-38
|
https://f1000research.com/articles/10-1242/v1
|
06 Dec 21
|
{
"type": "Research Article",
"title": "Factors Associated with Knowledge and Awareness of Stroke Among the Jordanian Population: A Cross-Sectional Study",
"authors": [
"Muna Barakat",
"Husam A. AlSalamat",
"Feras Jirjees",
"Hala Al-Obaidi",
"Zainab k. Hussain",
"Seif El Hadidi",
"Sara Mansour",
"Diana Malaeb",
"Hassan Hosseini",
"Husam A. AlSalamat",
"Feras Jirjees",
"Hala Al-Obaidi",
"Zainab k. Hussain",
"Seif El Hadidi",
"Sara Mansour",
"Diana Malaeb",
"Hassan Hosseini"
],
"abstract": "Background and objective: Stroke is the second leading cause of death in Jordan and over the world. Knowledge and awareness towards stroke play a crucial role in the management and prevention of its complications. This study aims to assess the knowledge and awareness about stroke among the Jordanian population and determine factors associated with stroke awareness. Methods: This cross-sectional study through a web-based anonymous questionnaire that needed 10 minutes to be completed. It examined sociodemographic characteristics and recognition of the risk factors, warning signs, stroke consequences, and early response to stroke symptoms. Logistic regression analysis identified the factors associated with poor knowledge of stroke. Results: A total of 573 Jordanian adults participated in this study. The participant's ability to identify at least one early symptom of stroke and the proper response to the symptoms were significantly correlated with the educational level (OR of 3.4 and 2.5, respectively). At least one consequence of stroke was significantly associated with different demographic factors such as gender, socioeconomic income, females versus males and those with medium income versus low income had significantly higher odds (OR of 6.6 and 4.1, respectively). Conclusion: This study revealed a good knowledge and awareness level about stroke among Jordanians correlated mainly with their educational level. Therefore, new strategies should be considered to decrease the prevalence of stroke in Jordan, including the need for engagement in enhanced awareness campaigns.",
"keywords": [
"Awareness",
"Factors",
"Knowledge",
"Jordan",
"Stroke"
],
"content": "Introduction\n\nStroke is the second cause of death worldwide, with approximately 11% of total deaths and is the leading cause of serious and permanent disability (WHO, 2020, Katan, 2018). Moreover, in the past decades, the prevalence of stroke has increased more in developing countries than in developed countries due to several recent changes in the segment of countries (Feigin VL, 2009, Roth GA, 2020). For instance, stroke represents a major cause of disability and death in the last three decades in Jordan as a large Middle Eastern country. This surge has been linked to the prevalence of behavioral risk factors such as smoking, insufficient physical activity, and an unhealthy diet (Vos et al., 2020, Ministry of Health, 2020).\n\nPrimary prevention of cerebrovascular accidents is essential to minimize stroke occurrence. It is achieved through different means, focusing on identifying associated risk factors, initiating prophylactic measures, and increasing patient awareness. Educational programs directed towards the community are among the best preventive measures; thus, an accurate assessment of comprehensive knowledge of stroke and its associated trigger factors is needed (Sug Yoon et al., 2001, Trobbiani et al., 2013, Hatzitolios et al., 2014, Morren and Salgado, 2013, Pandian et al., 2005). In addition to improving the patients’ quality of life, knowledge will prevent healthcare professionals from being overwhelmed when stroke cases present to the emergency room at an early stage (Awad and Al-Nafisi, 2014), noting that 80% of stroke cases are preventable if necessary precautions and actions are taken (Vincent-Onabajo et al., 2015).\n\nGlobally, there is a lack of knowledge about stroke modifiable risk factors as unhealthy behaviors, obesity, smoking, and uncontrolled chronic diseases (Medeiros et al., 2012, Boehme et al., 2017, Farrag et al., 2018). The accurate identification of stroke early symptoms is critical for quick and efficient medical interventions and the reduction of neuro-deficit complications as well as mortality (Müller-Nordhorn et al., 2006, Stroebele et al., 2011a). Hence, in Low-Middle Income and developing countries, there is always a question about the public's understanding of stroke’s risk factors and related issues in terms of the condition’s risk, morbidity and mortality (Stroebele et al., 2011c, Romero et al., 2008). Therefore, it is important to screen public characteristics and traits regarding lifestyle, behavior (O'Donnell et al., 2016), educational level, smoking habits (Hosseininezhad et al., 2017), and socioeconomic status (Hawkes et al., 2015, Hosseininezhad et al., 2017).\n\nSince stroke risk factors (i.e., history of hypertension or/and diabetes) are identifiable in individuals with low socioeconomic status, past medical history is also essential to investigate. Educational level, personal history of smoking, and high-income status have been associated with increased stroke knowledge (Ramírez-Moreno et al., 2016). Gender is another factor to consider, as findings are contradictory. Indeed, several studies reported that women are more likely to present non-traditional stroke warning signs, develop stroke, and go late to the emergency department compared to males (Lisabeth et al., 2009, Mandelzweig et al., 2006, Roger et al., 2012); oppositely, others showed that women recognize all the five traditional warning signs and quickly call the emergency department (Focht et al., 2014).\n\nAlthough the assessment of knowledge study deems simple, the outcomes of such research segment positively impact the design and implementation of highly effective interventions based on accurate population-based data. Yet, no nationwide study has been conducted in Jordan to assess the public awareness towards stroke. This study aims to highlight public’ gaps in knowledge and to reveal practice-related misconceptions in Jordan as a Middle-Eastern Developing country.\n\n\nMethods\n\nThis descriptive cross-sectional study was carried out on the Jordanian population across all regions, using an anonymous online survey. A snowball sampling method was applied to abide by the lockdown restrictions enforced by the Jordanian Government (2020). An electronic questionnaire was created on Google forms and distributed to the Jordanian internet users (n= 6.5 million) via digital platforms (i.e., WhatsApp, LinkedIn, and Facebook) and made available online from February 2021 to April 2021. Participation in this study was voluntary and anonymous. Participants above 18 years of age were eligible; those with a history of stroke were excluded. The anonymity of the participants was guaranteed during the data collection process. A written participant consent statement “Your participation in completing this questionnaire is highly appreciated” was given to the participants at the beginning of the survey. If the participants were willing to proceed with the survey, they approved their consent. If not, they selected “disagree to participate” and did not continue with the survey questions. Potential participants who completed the survey were considered to have given informed consent for their participation in the study. Ethics approval for the study was obtained from the Faculty of Pharmacy, Applied Science Private University, Amman, Jordan (Approval Number: 2021-PHA-9).\n\nBased on another study, which concluded that around 71.8% of the participants were able to identify at least 3 out of 5 stroke risk factors (Sadighi et al., 2018a), and in the absence of similar studies in Jordan, the Epi Info software version 7.2 (population survey) calculated a minimum sample of 312 participants at a confidence level of 95%. The reason for oversampling is to take into account patients’ refusal.\n\nThe questionnaire was in Arabic, the native language of Jordan and designed in a plain Arabic language. The expected filling time of the questionnaire is 20 minutes. This survey was developed based on previous literature (Sadighi et al., 2018b, Han et al., 2019b). Participants filled it out without the help of investigators to avoid any potential influence when answering the questions.\n\nThe first section of the questionnaire covered the sociodemographic and socioeconomic factors, including age, smoking status, marital status (married versus others), employment status (employed versus not employed), family income, residence (urban versus rural), educational level, past medical history (e.g., hypertension, diabetes mellitus, dyslipidemia). Age was categorized into four groups (18-29, 30-49, 50-70, and above 70 years). The family income per month was divided into three financial categories: low (<400 JOD), intermediate (400-1000 JOD), and high (>1000 JOD), as 1 JOD equals 1.4 US Dollars (Ahmed et al., 2019).\n\nThe second section assessed the general knowledge about stroke. Respondents answered the following statements: stroke 1) affects the brain, 2) is common among the elderly, 3) is contagious, 4) is hereditary, and 5) and can be prevented. This section also evaluated awareness about stroke risk factors, including hypertension, smoking, alcohol consumption, dyslipidemia, diabetes, physical inactivity, heart disorders, obesity, old age, and psychosocial stress. Moreover, it examined knowledge of early warning signs: 1) sudden numbness or weakness of the face, arms, or legs, especially on one side of the body; 2) sudden confusion or difficulty speaking or understanding speech; 3) sudden visual impairment in one or both eyes; 4) sudden difficulty walking, dizziness, or loss of balance or coordination; and 5) sudden severe headache with no known cause. Participants were awarded one point per correct answer to the above statements (Han et al., 2019a).\n\nStatistical analysis was performed using the Statistical Package for Social Sciences version (SPSS) 25.0. All continuous variables were presented as mean and standard deviation (SD), and categorical variables were presented as frequencies (n) and percentages (%). Binary logistic regression was performed to determine the factors associated with the ability to spontaneously answer at least one or more stroke risk factors, one or more warning signs, one or more consequences, and seeking an emergency room as soon as stroke develops. Variables with a p<0.2 in the bivariate analysis were included in the regression analysis. Results were presented as odds ratios (OR) and 95% CI. Statistical tests were two-tailed and reported statistically significant at p < 0.05.\n\n\nResults\n\nA total of 573 participants completed the questionnaire. Of which, 65.1% are females and 59.2% are married, Table 1. A total of 93.4% of participants had finished their third-level education, and 85.9% were living in urban areas. Regarding the medical history, the most reported concomitant diseases were dyslipidemia (21%), obesity (18%) and Hypertension (15.7%). 94.8% of the participants reported their familiarity with the term stroke, while 31.4% just knew the term when a family member had it.\n\nThe sample showed a satisfactory overall level of knowledge about stroke (Figure 1 and Table 2). Nearly 95% of the participants mentioned that the brain is the primary organ of the body affected by stroke and 81% were aware of its possible prevention. In the question about risk factors, 92.1% believed that high blood pressure is the most common risk factor of stroke, followed by psychosocial stress (90.1%) and dyslipidemia (86%), Figure 2. The most identified warning signs were “Sudden difficulty in speaking or understanding speech” as 92.3% and “Sudden weakness/numbness/tingling” as 88%, Figure 3.\n\nInternet/social media was the primary source of information about stroke as described by 24.4% of the respondents, followed by healthcare professionals as reported by 20.9% and family/relatives as 15.2%, Figure 4.\n\nA total of 37.2 % identified all the risk factors appropriately, 36% recognized all the symptoms, and 62.7% stated all possible consequences of stroke. A significantly higher proportion of participants who are residents of the urban areas versus rural (86.5% vs. 13.5%) correctly identified the risk factors. Moreover, a significantly higher proportion of participants with university level of education compared to scholar level (94% vs. 6%) and those with no history of diabetes compared to having diabetes (92.3% vs. 7.7%) recognized at least one warning symptom of stroke. A significantly higher proportion of females versus males (65.8% vs. 34.2%) and those residing in urban areas vs. rural areas (86.7% vs. 13.3%) correctly identified the consequences emerging from stroke (Table 3).\n\nIn terms of attitude, a significantly higher number of correct answers was associated with university compared to scholar level of education (94.3 % vs. 5.7%), who had a job versus unemployed (62.2% vs. 37.8%) and those with no history of diabetes compared to having diabetes (92.7% vs. 7.3%) (Table 4).\n\nWhen considering the identification of at least a risk factor as the dependent variable, the multivariable analysis showed that those residing in rural areas were less likely to identify a risk factor than those living in urban areas (OR = 0.2, p-value of 0.011).\n\nThe participant's ability to identify at least one early symptom of stroke as the dependent variable, university compared to the scholar level of education had significantly higher odds (OR = 3.4, p-value of 0.023), and diabetes was inversely associated with early symptoms identification (OR = 0.2, p-value of 0.008).\n\nWhen considering the identification of at least one consequence of stroke as the dependent variable, females versus males and those with medium income versus low income had significantly higher odds (OR of 6.6 and 4.1 respectively). Moreover, residents of rural areas were less likely to identify stroke consequences compared to urban residents (OR = 0.1, p-value of 0.005).\n\nConcerning the response to stroke symptoms (by taking the patient to the hospital) as the dependent variable, university compared to scholar level of education and employed versus unemployed had significantly higher odds (OR of 2.5 and 1.8 respectively) whereas, having diabetes was associated with lower odds compared to no diabetes history (OR = 0.4) (Table 5, Figure 5).\n\n\nDiscussion\n\nPublic health literacy is a strong asset for a healthier community. As of August 2020, The U.S. Department of Health and Human Services (HHS) released Healthy People 2030, introducing an updated definition of personal health literacy as “the degree to which individuals can find, understand, and use information and services to inform health-related decisions and actions for themselves and others,” while organizational health literacy describes the degree to which organizations equitably enable individuals to pursue personal health literacy (Services, 2020, Ancker et al., 2020). This study describes the levels of knowledge and awareness related to stroke among individuals from the general Jordanian population.\n\nMost participants in our study expressed excellent knowledge regarding stroke, particularly being related to the brain, not contagious, not old-age specific, not hereditary, and being preventable. Additionally, most participants identified at least one risk factor, one consequence, and one symptom related to stroke. Compared to similar literature (Sug Yoon et al., 2001, Pancioli et al., 1998, Croquelois and Bogousslavsky, 2006, Reeves et al., 2008), our outcome measures of stroke health literacy are higher, mainly that all knowledge, risk factors, symptoms, and consequences related to stroke were identified by more than 50% of the study sample.\n\nIn our study, 98.1% of participants identified at least one risk factor related to stroke. In comparison, previous studies have reported 85.4% among 390 participants in Lebanon (Khalil and Lahoud, 2020), 76.2% among 822 participants in Australia (Sug Yoon et al., 2001), and 59.6% among 2884 participants in Spain (Segura et al., 2003). Conversely, other previous studies have demonstrated poor knowledge of stroke risk factors and symptoms in the general population (Jones et al., 2010, Stroebele et al., 2011b, Nicol and Thrift, 2005). According to the latest 2021 update from the American Heart Association, risk factors related to stroke are high blood pressure, hyperglycemia, obesity, renal dysfunction, and hyperlipidemia, in addition to 47% being attributed to behavioral risk factors such as sedentary lifestyle, smoking, and an unhealthy diet (Alonso et al., 2021). At the same time, 30% were attributed to air pollution worldwide (Collaborators and Ärnlöv, 2020). Most identified risk factors related to stroke in our study were hypertension, psychological stress, hypercholesterolemia, smoking, and obesity, with percentages exceeding 80%. Unlike a previous 2014 Jordanian study of 1854 participants, which reported getting older (58.8%), previous stroke (56.6%), and hypertension (56.0%) as most commonly identified risk factors in their study (Madae’en et al., 2013). This shows a more confident trend in identifying risk factors related to stroke among our study participants. Moreover, hypertension (48.2%), followed by stress (43.1%), were identified as risk factors among participants in a study from Lebanon (43.1%) (Khalil and Lahoud, 2020). Similarly, among 469 participants in a study from Morocco, hypertension (55.7%), followed by stress (48.8%), were identified as risk factors for stroke (Kharbach et al., 2020b). Despite being one of the most common modifiable risk factors for stroke, Diabetes Mellitus was relatively less identifiable by our study participants (68.4%). This finding has been reported elsewhere in previous studies (Kharbach et al., 2020a).\n\nAlso, participants in our study expressed a higher percentage recalling at least one stroke symptom (95.5%) compared to studies in Portugal (74.2%) (Duque et al., 2015), Norway (70.7%) (Sundseth et al., 2014), Oman (68.0%) (Al Shafaee et al., 2006), Korea (65%) (Kim and Yoon, 1997), and Lebanon (68.2%) (Khalil and Lahoud, 2020). Similarly, in a previous 2014 study from Jordan, (87.3%) of participants identified at least one sign and symptom related to stroke, which is still relatively high. (Madae’en et al., 2013). Sudden difficulty speaking or understanding speech was the most frequently reported stroke symptom in our study (92.3%) compared to a previous study in Jordan (85.1%) (Madae’en et al., 2013), and Australia (14.2%) (Sug Yoon et al., 2001), and Ireland (54%) (Hickey et al., 2009). However, sudden weakening of one side of the body was reported as relatively the most prevalent stroke symptom, as among Omani (65 %) (Al Shafaee et al., 2006) and Nigerian (24.4%) populations (Wahab et al., 2008).\n\nRegarding their attitude toward stroke, participants in our study were encouraged to go to a hospital as soon as possible after a stroke is identified (89.0%), like a previous study that emphasized the need for immediate medical care for stroke patients (Khalil and Lahoud, 2020). Among 400 participants in an earlier study from Oman, 73% of participants reported they would immediately go to the hospital emergency if they suspected a stroke (Al Shafaee et al., 2006). However, percentages from international studies may vary, with only 47% claiming they would go to a hospital if they were suspicious of a stroke (Jones et al., 2010). Adequate knowledge about risk factors, symptoms, and consequences related to stroke in our study could be attributed to the younger age and high level of education of the participants.\n\nOur study findings showed that the female gender was attributed to better knowledge about stroke consequences than males, with no gender-specific difference in knowledge about risk factors and symptoms related to stroke. In a systematic review until 2008, the female gender was attributed to the better overall understanding of risk factors and symptoms related to stroke (Stroebele et al., 2011b). Another study explained the male gender as a predictor of enhanced knowledge (Wahab et al., 2008). Whether there are gender-specific variations in knowledge remains controversial and would need further in-depth causality assessments, as previous studies provide no consistent gender correlations in favor of such differences about stroke’s risk factors, symptoms, or consequences (Park et al., 2006, Koçer et al., 2006, Pontes-Neto et al., 2008). Nevertheless, women tend to be more knowledgeable, express greater interest in health topics, and even spend more time seeking information than men do (Horch and Wirz, 2005).\n\nMoreover, our results revealed that living in an urban area was significantly associated with better awareness of stroke risk factors and consequences; this could be attributed to better access to information resources and health services than rural ones (Joubert et al., 2008). In addition, participants who were well educated, employed, or diagnosed with diabetes in our study expressed willingness to promptly take a patient to hospital if they were suspicious of a stroke, which is somewhat expected, as better knowledge of consequences of a stroke would warrant prompt care. Furthermore, employment can warrant accessibility to seek medical help through insurance. While for diabetic patients, this might be attributed to their better knowledge of their disease status and consequences, as they often visit a healthcare provider for chronic medical care (Bogoshi, 2003, Chukwuocha et al., 2018).\n\nConcerning stroke information resources, no particular resource was regarded as major by the participants in our study, but rather relatively, the internet and social media (24.4%) were the most frequently used resource of information, followed by healthcare professionals (20.9%), and family or relatives (15.2%). This is rather alarming since publicly available health information across social media might not be evidence-based and often misinterpreted by the general public (Suarez-Lledo and Alvarez-Galvez, 2021, Waszak et al., 2018).\n\nSeveral limitations can be identified for this study. First, an online Google survey is subject to a security breach, yet password protection for editing privileges was implemented and accessible by the research team. Second, representation of the Jordanian population could be compromised, as the study tool warrants computer literacy, internet availability, an enhanced level of education to access and complete the online survey. Third, information bias related to the accessibility of resources on-demand can compromise response credibility. Fourth, selection bias related to the snowball collection technique might be an issue, with no random selection warranted. Residual confounding bias could arise from possible un-measured variables or responses to variables directly or indirectly related to stroke. Moreover, an online survey instead of a face-to-face meeting poses reliability and authenticity risks to the study data. The online survey included country-specific questions for Jordanians to complete, with a full description of the target population and inclusion criteria in the title and the invitation message. Considering the restriction measures during the COVID-19 pandemic, such a methodology was the best option.\n\n\nConclusion\n\nThe general Jordanian population expresses good overall personal health literacy about risk factors, symptoms, and consequences related to stroke. Higher education levels, living in an urban residential area, and being employed were attributed to better knowledge about various aspects of the stroke. Through structured, reliable, evidence-based, and accessible health awareness resources, organizational health literacy is warranted to target individuals with inadequate personal health literacy related to stroke among the Jordanian population. Further nationwide studies could affirm more representative findings to the general Jordanian population.\n\n\nData availability\n\nOpen Science Framework. Assessment of Knowledge, Awareness of Stroke, and the Factors Associated with Among Jordanian Population: A Cross-Sectional Study. DOI: https://doi.org/10.17605/OSF.IO/QZTV3.\n\nThis project contains the following data.\n\n• Raw Data spss.sav\n\n• STROBE_checklist_cross-sectional score.doc\n\n• Stroke Awareness Questionnaire Final.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthors' contributions\n\nAll authors were involved in all parts of the study and manuscript preparation, including literature search, study design, analysis of data, manuscript preparation, and review of the manuscript.",
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}
|
[
{
"id": "102098",
"date": "13 Dec 2021",
"name": "Nadeen Anabtawi",
"expertise": [
"Reviewer Expertise Pharmaceutical 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\nA well-written manuscript that assessed the knowledge and awareness of stroke among the Jordanian population. Despite the limitations, which have already been addressed by the authors, this manuscript gets to a great conclusion that is well supported by extensively analyzed data. I have some minor comments below that won’t affect the robustness of the manuscript, but they are just opportunities for improvement. Comments:\nThe novelty of this research is not clearly stated. Earlier research (Madae’en et al., 2013) with the same purpose, which is referenced by the author and results were compared. However, I suggest explaining what are the main points that this research will add to the previous knowledge about stroke awareness in the Jordanian population and emphasizing the meaningful contribution of this manuscript to the field. The study revealed a good knowledge and awareness level about stroke among Jordanians. However, “good” could be a vague term to use without further explanation. I suggest adding a description of what “good or satisfactory” exactly means and emphasizing the rating scale that resulted in such a conclusion. Is it compared to previous research and the percentage was improved, or there were specific criteria for rating the good and the bad knowledge? I assumed that the American Heart Associated stroke definition was used to generate the assessment criteria used for stroke knowledge. However, it would be more reasonable to clearly state the rationale behind choosing the assessment criteria used throughout the manuscript.\nOverall, this is an interesting study and the authors have collected and analyzed a good dataset using appropriate methodology. The paper is generally well written and structured, and I recommend it for 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?\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": "7604",
"date": "20 Dec 2021",
"name": "Muna Barakat",
"role": "Author Response",
"response": "Dear Dr. Nadeen Thank you for your great feedback and review. It was a pleasure to get your attention and we tried to address your fruitful comments carefully as the following: 1- The discussion section has been amended as requested. \"Although a similar study was previously conducted in Jordan by (Madae’en et al., 2013), which assessed the level of knowledge and awareness toward stroke among the general Jordanian population, this study did not evaluate the factors that exert an influential effect on stroke. Thus; our study provided insight into both the level of knowledge and awareness toward stroke and the factors associated with it.\" 2- The method section has been amended as required. \"According to the previous study by (Han et al., 2019a), participants were awarded one point per correct answer to the above statements, however, it lacks a cutoff value that identifies the acceptable level of knowledge. Thus, our study summed up the total correct answers and considered a good level of knowledge above 50%.\" 3. The definition that was utilized through the manuscript was in accordance with the definition set by the American heart association and it was applied among all manuscript sections."
},
{
"c_id": "7695",
"date": "13 Jan 2022",
"name": "Nadeen Anabtawi",
"role": "Reviewer Response",
"response": "Previous comments were properly addressed. I have no further comments and I see the final version is fit for publication."
}
]
},
{
"id": "102102",
"date": "14 Dec 2021",
"name": "Taher Hatahet",
"expertise": [
"Reviewer Expertise pharmacy education",
"community pharmacy",
"drug delivery and nanotechnology"
],
"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\nFactors Associated with Knowledge and Awareness of Stroke Among the Jordanian Population: A Cross-Sectional Study\nOverview:\nThe article investigates the awareness associated with stroke in Jordan. In Key words\n\nI suggest adding other key words like 'cross sectional study'.\nIn the introduction\nParagraph 1: there 2 refs not inserted as hyperlinks\n“recent changes in the segment of countries” should be further explained what happened exactly and are these changes seen in Jordanian context?\n\"noting that 80% of stroke cases are preventable if necessary precautions and actions are taken\" It is better to write it as a separate sentence: \"It is worth noting that...\"\n“past medical history is also essential to be investigated”\nParagraph 4: the talk about gender covered females but did not cover males.\nParagraph 5: please add the impact of the work in the scope of the region not only the country to highlight the article value to wider readers.\nMethod section\nStudy design\nIt is not clear to how many people the survey was sent to in total and what the method of contact through social media was. This should be made clearer - I don’t think the survey reached to all internet users in the country!\nSample size calculation I can see the relationship between being able to identify 3 out of 5 factors to sample size calculations?\nResults Figure 1 resolution is low, the figure should be inserted as a high resolution figure.\nDiscussion I think some of the limitation mentioned at the limitation section should be also introduced to the discussion of results especially when presenting much higher awareness of stroke in the sample population in Jordan compared to other countries.\nIt is advisable to discus not simply the questions of the survey but also the type of sample taken. Like when talking about identification of at least one risk factor. We can see the very high % in Jordan compared to Spain which I think is coming for the type of sample and this should be added to discussion. The same applies to recalling at least one stroke symptom.\nIn paragraph 7: there should be more comparison to literature from the same geographic area to see if the same findings were reported, like in Lebanon or Saudi Arabia, do people living in rural areas score lower in stroke questionnaires than in urban ones? etc.\nI hope that the author would improve on the comments but keeping in mind that the paper is of good quality. I consider Approved with Reservations to be too much for my comments.\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": "7606",
"date": "20 Dec 2021",
"name": "Muna Barakat",
"role": "Author Response",
"response": "Dear Dr Taher: Thank you for your great feedback and review. We appreciate your efforts and comments and we tried to address them carefully. In Key words I suggest adding other key words like 'cross sectional study'. R: Done In the introduction Paragraph 1: there 2 refs not inserted as hyperlinks R: Done “recent changes in the segment of countries” should be further explained what happened exactly and are these changes seen in Jordanian context? R: This sentence has been removed \"noting that 80% of stroke cases are preventable if necessary precautions and actions are taken\" It is better to write it as a separate sentence: \"It is worth noting that...\" R: Done “past medical history is also essential to be investigated” R: Done Paragraph 4: the talk about gender covered females but did not cover males. R: he discussion was tailored to the influence of female gender as the results were significant for the influence of female rather than male. Paragraph 5: please add the impact of the work in the scope of the region not only the country to highlight the article value to wider readers. R: The following was added \" . The study will provide an overall insight towards importance of raising the level of knowledge and awareness towards stroke to minimize stroke development, to prevent stroke recurrence, and ensure early patient presentation\" Method section Study design It is not clear to how many people the survey was sent to in total and what the method of contact through social media was. This should be made clearer - I don’t think the survey reached to all internet users in the country! R: The questionnaire link was sent through social media networks to gather the largest number of responses, however, through this means of communication we are not able to know the exact number of received invitations. Sample size calculation I can see the relationship between being able to identify 3 out of 5 factors to sample size calculations? R: Based on a search that was performed to identify the highly related study to be able to calculate the target sample size, we identified the study conducted by (Sadighi et al., 2018a). Results Figure 1 resolution is low, the figure should be inserted as a high resolution figure. R: A new Figure will be uploaded. Discussion I think some of the limitation mentioned at the limitation section should be also introduced to the discussion of results especially when presenting much higher awareness of stroke in the sample population in Jordan compared to other countries. R: The discussion section has been modified \" Although Karasneh et al 2020 mentioned in their study that Jordanians have an inadequate level of health literacy, most of the participants in our study expressed good knowledge regarding stroke (Karasneh et al., 2020).\" It is advisable to discus not simply the questions of the survey but also the type of sample taken. Like when talking about identification of at least one risk factor. We can see the very high % in Jordan compared to Spain which I think is coming for the type of sample and this should be added to discussion. The same applies to recalling at least one stroke symptom. R: It is mentioned in the discussion \" In our study, 98.1% of participants identified at least one risk factor related to stroke. In comparison, previous studies have reported 85.4% among 390 participants in Lebanon (Khalil and Lahoud, 2020), 76.2% among 822 participants in Australia (Sug Yoon et al., 2001), and 59.6% among 2884 participants in Spain (Segura et al., 2003). Conversely, other previous studies have demonstrated poor knowledge of stroke risk factors and symptoms in the general population (Jones et al., 2010, Stroebele et al., 2011a, Nicol and Thrift, 2005).\" In paragraph 7: there should be more comparison to literature from the same geographic area to see if the same findings were reported, like in Lebanon or Saudi Arabia, do people living in rural areas score lower in stroke questionnaires than in urban ones? etc. R: In the discussion section \"Moreover, our results revealed that living in an urban area was significantly associated with better awareness of stroke risk factors and consequences; this could be attributed to better access to information resources and health services than rural ones (Joubert et al., 2008). Similar findings were revealed by Alluqmani 2021 in Saudi Arabia, as they also recommended for comprehensive investigation for stroke awareness, including large samples in rural populations (Alluqmani et al., 2021).\""
}
]
},
{
"id": "102097",
"date": "15 Dec 2021",
"name": "Abdelrahim Alqudah",
"expertise": [
"Reviewer Expertise Diabetes and cardiovascular 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\nThis paper discusses factors associated with knowledge and awareness of stroke among the Jordanian population which is an important topic that gives new insight about this serious complication.\nI would like to thank the authors for the great flow of their introduction. They started their introduction by giving information about stroke and its prevalence worldwide, then they focused on the effect of good knowledge and awareness of the population on the prevention of cerebrovascular events resulting from stroke. After that, they raised the issue of lack of knowledge and awareness among the population and how this can increase the risk of this serious event which supports the aim of their research.\n\nThe study design was very good. The snowball method is a good technique to increase the response rate. The authors followed the ethical considerations in their data collection procedure. The response rate (573) is considered very good and above the required number. The used instrument was very good and well-prepared to cover the sociodemographic and knowledge levels. Their statistical model was good which used frequencies, descriptive stats and logistic regression to predict the factors affecting population knowledge about stroke. The figures and tables represented the results in a great way which makes the results clear and easy to understand. The discussion was well-structured and concise and explained all the related points mentioned in the results section.\nThis study concluded that the knowledge was affected by education level, living in urban areas, and being employed, therefore, targeting a population with inadequate knowledge about stroke could reduce the risk of stroke and its complications.\nI think the results of this study will give new insights for the government to focus more on the awareness campaigns about stroke. So, I would recommend the publication of this study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": "7603",
"date": "20 Dec 2021",
"name": "Muna Barakat",
"role": "Author Response",
"response": "Dear Dr Abdlarahim Thank you for your great feedback and review. It was a pleasure to get your attention to our work."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1242
|
https://f1000research.com/articles/10-507/v1
|
28 Jun 21
|
{
"type": "Review",
"title": "Novel antifungal agents in clinical trials",
"authors": [
"Samantha E. Jacobs",
"Panagiotis Zagaliotis",
"Thomas J. Walsh",
"Panagiotis Zagaliotis",
"Thomas J. Walsh"
],
"abstract": "Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We examine three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.",
"keywords": [
"Antifungal Agents",
"novel treatments",
"pharmacokinetic and pharmacodynamic",
"clinical trials"
],
"content": "Introduction\n\nInvasive fungal diseases (IFDs) are a growing public health concern in an expanding population of immunocompromised hosts1. Three classes of antifungal drugs are currently available for prevention and treatment of IFDs: triazoles, polyenes, and echinocandins. However, use of these agents is often hampered by drug toxicity, drug-drug interactions, and lack of oral formulation. Furthermore, novel therapeutic options are needed due to increasing rates of antifungal resistance and increasing IFDs due to emerging pathogens, many of which are resistant to approved antifungal agents. Herein, we review the antifungal pipeline for agents in clinical phases of development. We give particular attention to investigational drugs with novel mechanisms targeting cellular and biochemical pathways.\n\n\nAgents targeting the cell wall\n\nMechanism of action. Glycosylphosphatidylinositol (GPI)-anchored mannoproteins are one of the major cell wall components of fungi. Inhibition of GPI-anchored protein biosynthesis therefore has the potential to compromise cell wall integrity and restrict fungal growth. Fosmanogepix (previously APX001 and E1210; Eisai Company, Japan) is a first-in-class antifungal prodrug that inhibits the fungal Gwt1 (GPI-anchored wall protein transfer 1) gene that encodes a new acyltransferase involved in an early step of the GPI post-translational biosynthetic pathway2. Fosmanogepix undergoes rapid and complete metabolism by systemic phosphatases to its active moiety, manogepix. The chemical structure, mechanism of action, spectrum of activity, clinical trials status, and potential advantages of fosmanogepix and other investigational antifungal agents included in this review are provided in Table 1.\n\nIFI, invasive fungal infection; VVC, vulvovaginal candidiasis\n\nActivity in vitro and in vivo. Fosmanogepix has broad-spectrum activity against a range of yeasts and molds. Potent in vitro activity is demonstrated against most Candida species with the exception of Candida krusei2. Fosmanogepix also shows in vitro activity against fluconazole-resistant Candida species, including C. auris, as well as echinocandin-resistant C. albicans and C. glabrata with fks mutations2–5. Among 16 C. auris isolates from Europe and Asia, fosmanogepix demonstrated a minimum inhibitory concentration (MIC) required to inhibit growth of 90% of organisms (MIC90) value that was 8-fold lower than that of anidulafungin, the next most active agent. Highly potent in vitro activity was also observed in six pan-resistant C. auris isolates from New York (MIC range 0.008 µg/mL to 0.015 µg/mL)6. Furthermore, in a neutropenic mouse model of disseminated C. auris, treatment with fosmanogepix led to significantly improved survival and decreased fungal burden in brain tissue as compared to anidulafungin5. Fosmanogepix also was shown to have efficacy in treatment of experimental Candida endophthalmitis and hematogenous meningoencephalitis7.\n\nFosmanogepix has activity against Cryptococcus neoformans and C. gattii, as well as Coccidioides species8,9. In mice with cryptococcal meningitis, the combination of fosmanogepix and fluconazole was observed to decrease fungal burden in a synergistic manner in brain tissue but not in lung tissue9.\n\nAmongst moulds, fosmanogepix has in vitro activity against a range of hyaline moulds including Aspergillus spp., Fusarium spp., Scedosporium spp., Lomentospora prolificans, and Purpureocillium lilacinum2,3,10. These organisms pose formidable therapeutic challenges, particularly in immunocompromised patients11. In immunocompromised mouse models of invasive pulmonary aspergillosis, hematogenously disseminated fusariosis, and pulmonary scedosporiosis, fosmanogepix demonstrated improved survival and tissue clearance versus placebo; whereas, comparable outcomes were observed between mice treated with fosmanogepix and posaconazole (Aspergillus-infected mice) or high dose liposomal amphotericin B (Fusarium- and Scedosporium-infected mice)12,13. Fosmanogepix also has activity against fungi in the order Mucorales (MIC ranges of 1 to 8 µg/mL). In a mouse model of pulmonary mucormycosis with two strains of Rhizopus arrhizus [minimum effective concentration (MEC) values of 0.25µg/mL and 4 µg/mL], fosmanogepix lead to improved survival and reduced lung and kidney fungal burden compared to placebo and similar outcomes as compared to isavuconazole14.\n\nPharmacokinetics/pharmacodynamics. Fosmanogepix is available in oral and intravenous (IV) formulations, achieving more than 90% bioavailability in humans. In rats and monkeys administered fosmanogepix via oral or IV route, rapid and extensive absorption to most tissues including lung, brain, liver, kidney, and eye were observed. Elimination was primarily biliary (rats) and fecal (monkeys)15. In phase 1 studies, plasma exposure to fosmanogepix was linear and dose proportional with a half-life of approximately 2.5 days16. Fosmanogepix was well-tolerated; there was no dose-limiting toxicity, and the most common adverse event was headache16. A phase 1b study of fosmanogepix safety and pharmacokinetics in patients with acute myeloid leukemia is completed, but results are not yet available (NCT03333005).\n\nClinical development. Clinical development of fosmanogepix has thus far focused on its role in the treatment of infections due to Candida spp., Aspergillus spp., and rare moulds. The U.S. Food and Drug Association (FDA) has granted Fast Track, Qualified Infectious Disease Product (QIDP), and orphan drug designation to fosmanogepix for the following indications: treatment of invasive candidiasis, invasive aspergillosis, scedosporiosis, fusariosis, mucormycosis, cryptococcosis, and coccidioidomycosis. Phase 2 trials are ongoing for the treatment of IFDs caused by Aspergillus spp. or rare moulds (NCT04240886), treatment of candidemia or invasive candidiasis due to C. auris (NCT04148287), and treatment of candidemia in non-neutropenic patients (NCT03604705).\n\nMechanism of action. Similar to the echinocandins, ibrexafungerp (previously MK-3118 and SCY-078; Scynexis, Jersey City, NJ, USA) disrupts fungal cell wall synthesis through inhibition of (1→3)-β-D-glucan synthase with fungicidal activity against Candida spp. However, ibrexafungerp is structurally distinct as a semisynthetic derivative of the naturally occurring hemiacetal triterpene glycoside enfumafungin that incorporates a pyridine triazole at position 15 of the core phenanthropyran carboxylic acid ring system and a 2-amino- 2,3,3-trimethyl-butyl ether at position 14 to enhance its antifungal potency and pharmacokinetic properties; thus, representing the first compound in the novel class of triterpenoid antifungals17. As compared to echinocandins, ibrexafungerp has distinct advantages of oral bioavailability, broad activity against pan-resistant C. auris, and maintaining activity against most echinocandin-resistant Candida spp.\n\nActivity in vitro and in vivo. Ibrexafungerp exhibits potent fungicidal activity against Candida species, including C. glabrata and multiple clades of C. auris18–20. Notably, ibrexafungerp retains in vitro activity against most echinocandin-resistant C. glabrata with fks mutations (MIC mode, MIC50, and MIC90 of 0.25µg/mL, 0.25µg/mL, and 1.0µg/mL, respectively)21. Amongst C. auris isolates with echinocandin resistance or pan-antifungal resistance, ibrexafungerp demonstrates MIC ranges from 0.25µg/mL to 1µg/mL and 0.12µg/mL to 1µg/mL, respectively19,22,23. In addition, C. auris biofilms treated with ibrexafungerp show reduced metabolic activity and thickness as compared to untreated control biofilms24.\n\nIbrexafungerp has fungistatic activity against Aspergillus species (MIC range <0.06µg/mL to 32µg/mL, MIC50 8µg/mL, MIC90 16µg/mL)25. The combination of ibrexafungerp with voriconazole, amphotericin B, or isavuconazole demonstrates in vitro synergy against wild-type (WT) Aspergillus species but not against azole-resistant strains25. Little in vitro activity is observed with ibrexafungerp against the Mucorales and non-Aspergillus hyaline moulds (Fusarium spp, Scopulariopsis spp, Lomentospora prolificans) with the exception of Paecilomyces variotii (MEC <0.02µg/mL to 0.03µg/mL)26. However, synergistic interaction between ibrexafungerp and isavuconazole is observed in vitro against Cunninghamella bertholletiae, S. apiospermum, F. solani and F. oxysporum; whereas, indifference or antagonism are observed with Mucor circinelloides and Rhizopus species, respectively27.\n\nIn a murine invasive candidiasis model with WT and echinocandin-resistant (ER) C. glabrata, ibrexafungerp significantly reduced kidney fungal burden in both groups as compared to placebo. In contrast, caspofungin administered by intraperitoneal injection reduced fungal burden in the WT group but not the ER group28. Reduced tissue fungal burden and improved survival with ibrexafungerp versus control also were observed in immunocompromised mice with disseminated C. auris29.\n\nIn a murine model of disseminated aspergillosis, treatment with ibrexafungerp led to significant reduction in Aspergillus kidney burden and serum galactomannan (GM) levels and improved survival as compared to control30. This in vivo activity of ibrexafungerp was observed in both wild type and azole-resistant isolates of A. fumigatus.\n\nThe combination of ibrexafungerp and isavuconazole also demonstrates synergy in a neutropenic rabbit model of experimental invasive pulmonary aspergillosis. As compared to isavuconazole alone, mice treated with ibrexafungerp and isavuconazole had significantly improved survival, decreased pulmonary infarct scores, and diminished serum GM levels31.\n\nIbrexafungerp is also efficacious in a murine model of Pneumocystis murina pneumonia, in which reductions in asci burden and improvements in survival were similar to those of trimethoprim-sulfamethoxazole and significantly better than in untreated controls32.\n\nPharmacokinetics/pharmacodynamics. Ibrexafungerp is orally bioavailable and highly protein bound (~99.6%) in humans. The maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increase approximately 20% with high fat meals33. It has a large volume of distribution in mice, rats, and dogs. Concentration in multiple tissues including liver, spleen, lungs, bone marrow, kidney, and skin exceeds that of plasma. However, there is low distribution to central nervous system (CNS) tissue34. In rats, approximately 90% of drug is eliminated in feces and bile, and 1.5% eliminated in urine34. Ibrexafungerp is a substrate of CYP3A and P-glycoprotein, though it neither induces or nor inhibits CYP3A. When ibrexafungerp and tacrolimus are co-administered, there is a 1.4-fold increase in AUC and no change in tacrolimus Cmax35. Thus, initial tacrolimus dose adjustment is not needed when co-administered with ibrexafungerp.\n\nClinical development. Ibrexafungerp will likely play an important role in management of invasive candidiasis due to WT and resistant Candida species and invasive aspergillosis; the drug has received QIDP and orphan drug designations for both indications.\n\nIn a phase 2 open-label, randomized study, 27 patients with invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of ibrexafungerp (1000mg loading dose followed by 500mg daily or 1250mg loading dose followed by 750mg daily) or standard of care (SOC) following initial echinocandin therapy. Similar rates of adverse events were observed across study arms; study-drug related treatment-emergent adverse events were reported in two patients (vomiting and diarrhea) and did not require drug discontinuation. There was no difference in favorable global response rates (clinical and microbiologic): 86%, 71%, and 71% in the ibrexafungerp 750mg, ibrexafungerp 500mg, and SOC arms, respectively, although the study was not powered to detect statistical superiority36.\n\nA phase 3 open-label, single arm study of ibrexafungerp in patients with refractory or intolerant fungal diseases is ongoing (FURI; NCT03059992). An interim analysis was performed in 20 patients with proven or probable invasive candidiasis (N=11) or severe mucocutaneous candidiasis (N=9). Eleven (55%) patients achieved a complete or partial response and 6 (30%) had stable disease. The most common treatment-related adverse events were gastrointestinal37. Target enrollment is 200 patients, and the estimated study completion date is December 2021.\n\nIbrexafungerp has also been studied for the treatment of vulvovaginal candidiasis (VVC). Day 10 and day 25 clinical cure and mycological eradication rates were similar or improved with ibrexafungerp 300mg twice daily x 2 doses compared to fluconazole 150mg x 1 dose. Diarrhea was the most common adverse event in the ibrexafungerp arm, observed in 10% of subjects38. An new drug application has since been submitted for treatment of VVC.\n\nOther ongoing clinical trials include a multicenter, randomized, double-blind study to evaluate the efficacy and safety of ibrexafungerp and voriconazole in patients with invasive pulmonary aspergillosis (NCT03672292). Ibrexafungerp is also in open-label clinical trials in India and the United States for treatment of Candida auris infection (CARES; NCT03363841). Thus far, outcomes of two patients enrolled in the CARES Study have been reported; both had C. auris bloodstream infections and were successfully treated with ibrexafungerp39.\n\nCombination antifungal therapy with a cell wall active agent and an antifungal triazole is a potentially important strategy in treatment of invasive aspergillosis [33]. Ibrexafungerp may develop a key role in combination antifungal therapy with an antifungal triazole in treatment of invasive aspergillosis. Simultaneous administration of an orally administered triazole and ibrexafungerp may allow patients to receive the potential therapeutic benefit of combination therapy in treatment of invasive pulmonary aspergillosis on an ambulatory basis.\n\nMechanism of action. Rezafungin (formerly SP3025 and CD101; Cidara Therapeutics, San Diego, CA, USA) is a novel agent in the echinocandin antifungal drug class that inhibits (1→3)-β-D-glucan synthesis. Rezafungin is a structural analogue of anidulafungin but it is differentiated by a choline moiety at the C5 ornithine position, conferring increased stability and solubility40. Due to its long half-life, rezafungin has the advantage of once weekly dosing as compared to other drugs within the echinocandin class that require daily dosing.\n\nActivity in vitro and in vivo. Rezafungin has potent in vitro activity that mirrors that of other echinocandins against WT and azole-resistant Candida species, as well as WT and azole-resistant Aspergillus species41–43. In immunocompromised mouse models of C. albicans and A. fumigatus infection, decreased fungal tissue burden and improved 10-day survival, respectively, were observed with rezafungin as compared to controls44. Rezafungin also had activity in a mouse model of disseminated C. auris, leading to decreased fungal tissue burden as compared to amphotericin B and control45. Furthermore, rezafungin was efficacious as prophylaxis against Pneumocystis in a mouse model, supporting its potential for development for prevention of Pneumocystis pneumonia in immunocompromised hosts46.\n\nPharmacokinetics/pharmacodynamics. Similar to other echinocandin drugs, rezafungin demonstrates a concentration-dependent pattern of fungicidal activity. Therefore, a front-loaded dosing regimen conferring higher plasma drug exposure may theoretically enhance pathogen killing and raise the barrier to drug resistance47. In phase 1 ascending dose studies evaluating single doses up to 400mg and multiple doses up to 400mg once weekly for 3 weeks in healthy adults, rezafungin demonstrated dose-proportional plasma exposures, long half-life (approximately 80 hours after the first dose and 152 hours after the third dose), and minimal renal excretion48. The Cmax ranged from ~5 µg/mL with the 100mg dose to ~22 to 30 µg/mL with the 400mg dose. Overall, rezafungin was well tolerated. There were no serious adverse events; most adverse events were mild and gastrointestinal (constipation and nausea). Mild infusion reactions characterized by nausea, flushing, and chest discomfort were also observed, most often with the third dose of 400mg of rezafungin. These reactions resolved within minutes without drug interruption or discontinuation.\n\nClinical development. Rezafungin has received U.S. FDA QIDP and Fast Track designations for prevention of invasive fungal infections as well as QIDP, Fast Track, and orphan drug designations for treatment of invasive candidiasis.\n\nA phase 2 multicenter, randomized, double-blinded trial in 207 adult patients with candidemia and/or invasive candidiasis compared the efficacy and safety of treatment with rezafungin versus caspofungin with fluconazole stepdown once clinically stable (STRIVE; NCT02734862)49. Patients were randomized to one of three treatment arms: rezafungin 400mg once weekly, rezafungin 400mg on week 1, then 200mg weekly, and caspofungin 70mg loading dose followed by 50mg daily for ≤4 weeks. The primary endpoint was overall cure, defined as resolution of signs of candidemia or invasive candidiasis and mycological eradication at day 14. The study was not designed for statistical comparison of the efficacy assessment, but overall cure rates and 30-day mortality, respectively, were similar across groups: rezafungin 400mg weekly (60.5% and 15.8%), rezafungin 400mg/200mg weekly (76.1% and 4.4%), and caspofungin (67.2% and 13.1%). In patients with candidemia, blood cultures cleared in 19.5 and 22.8 hours in the rezafungin and caspofungin groups, respectively. Rezafungin was also well-tolerated. The most common adverse events – hypokalemia, diarrhea, and vomiting – were observed in similar proportions of patients in the rezafungin and caspofungin groups. Study drug-related serious adverse events occurred in one patient in each rezafungin group and two patients in the caspofungin group.\n\nBased on the promising results of STRIVE, a phase 3 clinical trial of rezafungin versus caspofungin for treatment of candidemia and invasive candidiasis is ongoing (ReSTORE; NCT03667690). Another ongoing phase 3 trial compares rezafungin to standard of care for prevention of IFD due to Candida spp., Aspergillus spp., and Pneumocystis in patients undergoing allogeneic hematopoietic cell transplantation (ReSPECT; NCT04368559). The primary outcome is fungal-free survival at Day 90. In both phase 3 trials, rezafungin is dosed 400mg for the first week followed by 200mg once weekly.\n\n\nAgents targeting the cell membrane\n\nMechanism of action and pharmacology. Amphotericin B (AmB), a polyene antifungal agent, disrupts fungal cell wall synthesis by binding to ergosterol to form pores that allow leakage of intracellular contents, resulting in potent fungicidal activity against a wide range of yeasts and moulds. However, AmB and its lipid formulations are only available via intravenous injection due to low solubility, a tendency to self-aggregate in aqueous media, and low permeability50. Encochleated AmB (CAmB; Matinas BioPharma, Bedminster, NJ, USA) is a novel formulation that allows for oral administration with reduced toxicity. Cochleates form a multilayered structure composed of a negatively charged lipid (phosphatidylserine) and a divalent cation (calcium). This structure protects AmB from degradation within the gastrointestinal tract51. AmB is released to the fungus only when the cochleates interact with the target cells and subsequently destabilize in the setting of low intracellular calcium concentration.\n\nActivity in vitro and in vivo. Comparable in vitro activity against Candida spp. and Aspergillus spp. are observed with CAmB and deoxycholate AmB52,53. CAmB has been successfully administered in immunocompromised mouse models of disseminated C. albicans infection and disseminated aspergillosis. In both studies, oral CAmB and intraperitoneal deoxycholate amphotericin B demonstrated similar improvement in survival and reduction in tissue fungal burden as compared to untreated control animals52,54. Furthermore, CAmB was evaluated in a mouse model of cryptococcal meningoencephalitis where CAmB plus flucytosine had similar efficacy to parenteral AmB plus flucytosine and demonstrated potent activity55.\n\nPharmacokinetics/pharmacodynamics. A single dose of CAmB demonstrates extensive tissue distribution and penetration into target tissues in animal models56. In a phase 1 study in healthy adults evaluating escalating doses of 200, 400, and 800mg, CAmB was well tolerated at doses of 200mg and 400mg. The most common adverse events were gastrointestinal, occurring in 6%, 38%, and 56% of patients in the 200mg, 400mg, and 800mg groups, respectively. There were no serious adverse events or renal toxicity observed. Dose-dependent increases in Cmax and AUC were observed, comparable to those of animal toxicity studies57.\n\nClinical development. A phase 2a single-arm study of CAmB for refractory mucocutaneous candidiasis is ongoing (NCT02629419). Preliminary results indicate that all enrolled patients met the primary endpoint of ≥ 50% improvement in clinical signs and symptoms. CAmB was well tolerated at 400mg and 800mg with no observed renal or hepatic toxicity. In a phase 2 study of CAmB 200mg and 400mg and fluconazole 150mg for VVC in 137 patients, lower rates of clinical cure and more adverse events were observed with CAmB 200mg and 400mg as compared to fluconazole (NCT02971007). There were no serious adverse events58. Phase 1 and 2 studies of CAmB for treatment of cryptococcal meningitis in HIV-infected patients in Uganda are ongoing (EnACT; NCT04031833). CAmB has FDA-granted Fast Track, QIDP, and orphan drug designations for treatment of invasive candidiasis and aspergillosis, prevention of IFDs in patients on immunosuppressive therapy, and treatment of cryptococcosis.\n\nMechanism of action. Second-generation triazole antifungal agents, such as voriconazole, are highly effective against a range of yeasts and moulds; however, they are associated with significant drug-drug interactions due to off-target inhibition of human cytochrome P450 enzymes. Oteseconazole (VT-1161), VT-1598, and VT-1129 (Mycovia Pharmaceuticals, Inc., Durham, NC, USA) are next-generation azoles in which selective inhibition of the fungal enzyme CYP51 is more readily achieved by replacing the 1-(1,2,4-triazole) metal-binding group with a tetrazole59.\n\nActivity in vitro and in vivo. Oteseconazole, VT-1598, and VT-1129 have potent in vitro activity against Cryptococcus spp. and Candida spp. including C. krusei and fluconazole- and echinocandin-resistant C. glabrata60,61. VT-1598 has the broadest spectrum, which includes C. auris, moulds (Aspergillus spp. and Rhizopus spp.) and endemic dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides posadasii, and C. immitis)62–64. In murine models of CNS coccidioidomycosis, VT-1598 treatment leads to improved survival and reduced fungal burden in brain tissue as compared to fluconazole. Oteseconazole has similarly demonstrated efficacy in murine models of pulmonary and CNS coccidioidomycosis as well as disseminated mucormycosis due to Rhizopus arrhizus var. arrhizus65,66.\n\nClinical development. The FDA has granted QIDP, fast track, and orphan drug designation to VT-1598 for the treatment of coccidioidomycosis (Valley fever)67. VT-1598 is in phase 1 studies (NCT04208321). Oteseconazole is in phase 3 clinical trials for treatment of recurrent vaginal candidiasis (NCT02267382, NCT03562156, NCT03561701) after demonstrating safety and efficacy in a phase 2 study and has FDA QIDP and Fast-Track designations for this indication68. A phase 2 trial for toenail onychomycosis demonstrated higher week 48 cure rates with oteseconazole (32 to 42%) versus placebo (0%) (NCT02267356)69. In these completed trials, oteseconazole was well-tolerated with no evidence of hepatotoxicity or QT prolongation.\n\nMechanism of action. As compared to systemic therapy, aerosolized delivery of antifungal agents to the lung results in higher concentrations in epithelial lining fluid and bronchoalveolar lavage fluid; however, for successful activity, drug levels must be sustained in lung tissues with minimal systemic absorption70. PC945 (Pulmocide, London, United Kingdom) is a novel triazole antifungal agent that is being developed specifically for inhaled administration for treatment and prevention of invasive fungal infections of the sinopulmonary tract. The structure of PC945 is similar to but distinct from that of posaconazole. The structures are similar in having 2,4-difluorophenyl and 1H-1,2,4-triazole substitutions on the asymmetric carbon atom. However, PC945 differs structurally in having a central oxolane ring (in place of the dioxalane ring) and a long hydrophobic 3-ylmethoxy-3-methylphenyl[piperazin-1-yl]-N-(4-fluorophenyl)benzamide substitution. This hydrophobic moiety likely contributes to the sustained intrapulmonary concentrations of PC945.\n\nActivity in vitro and in vivo. PC945 has in vitro activity against azole-susceptible A. fumigatus [median MIC 0.031µg/mL (IQR 0.02 – 0.031µg/mL)] and most azole-resistant A. fumigatus71. Activity against A. terreus is comparable to posaconazole and more potent than that of voriconazole; however, PC945 has poor in vitro activity against A. flavus and A. niger. PC945 lacks activity against most Mucorales; although a MIC 2µg/mL was observed for Rhizopus oryzae71. Against Candida albicans (both azole-susceptible and azole-resistant strains), C. glabrata, and C. krusei, PC945 is generally more active than voriconazole and shares equal potency with posaconazole71. Using a global collection of 50 clinical Candida auris isolates, PC945 had more potent in vitro activity than posaconazole, voriconazole, and fluconazole [PC945 GM MIC (MIC50, MIC90): 0.14µg/mL (0.13, 1µg/mL)]72.\n\nAn in vitro model of the human alveolus has been developed to better understand the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of GM and outcomes of antifungal therapy73. Using this model, combination therapy with apical PC945 and basolateral posaconazole or voriconazole for azole-susceptible and azole-resistant A. fumigatus demonstrated synergistic activity as compared to either agent alone74.\n\nThe therapeutic potential of intranasal PC945 has been investigated in transiently neutropenic mice with invasive pulmonary aspergillosis. Intranasal PC945 leads to reduced concentrations of GM in bronchoalveolar lavage fluid (BALF) and serum and improved survival as compared to controls, and reduced GM concentration and similar survival as compared to intranasal posaconazole71,75. Combination therapy with intranasal PC945 and oral posaconazole was also evaluated in immunocompromised neutropenic mice with azole-susceptible A. fumigatus infection. Suboptimal dosages of PC945 and posaconazole were administered simultaneously, (i.e., doses at which either agent alone led to zero survival at Day 7), and Day 7 survival improved to 83%74. As a potential prophylactic agent, PC945 was administered in the same A. fumigatus-infected mouse model from days -7 to +3 and days -1 to +3. Extended prophylaxis (days -7 to +3) yielded greater inhibition of fungal load in lung tissue and GM concentrations in BALF and serum as compared to shorter duration, suggesting that the antifungal effects of PC945 accumulated in the lung upon repeat dosing75.\n\nPharmacokinetics/pharmacodynamics. Using the human alveolus, topical PC945 demonstrates sustained residency and antifungal activity in epithelial cells74.\n\nClinical development. A phase 1 trial of PC945 in 29 healthy subjects and patients with mild asthma is completed; results are not yet available on clinicaltrials.gov (NCT02715570). A phase 3 study of PC945 for adults, who have limited or no alternative treatment options, for the treatment of invasive pulmonary aspergillosis as part of a combined antifungal regimen is planned to start in 2021.\n\nIn a report of two lung transplant recipients with bronchial anastomotic masses due to A. fumigatus, PC945, administered in combination with systemic antifungal agents, was well-tolerated, and clinical resolution of infection was observed76.\n\n\nAgents targeting nucleic acid metabolism\n\nMechanism of action. Olorofim (previously F910318, discovered by F2G Ltd, Australia), a member of the novel antifungal class, orotomides, is in an inhibitor of the pyrimidine biosynthesis fungal enzyme dihydroorotate dehydrogenase. Interruption of pyrimidine synthesis impairs nucleic acid production and leads to the arrest of hyphal extension77.\n\nActivity in vitro and in vivo. Olorofim is unique among existing antifungal agents in that it has no activity against Candida species. Rather, olorofim has potent activity in vitro against WT and azole-resistant Aspergillus spp., some other highly resistant hyaline moulds, and Coccidioides spp.78 Amongst 133 azole-resistant A. fumigatus isolates due to TR34/L98H,TR46/Y121F/T289A, cyp51A-associated point mutations, or unknown resistance mechanisms, MIC range was 0.031µg/mL to 0.125µg/mL, 0.062µg/mL to 0.25µg/mL, and 0.01µg/mL to 0.125µg/mL, respectively79. Several studies have also shown excellent activity in vitro against Scedosporium species (MIC50/MIC90 0.06/0.25µg/mL) and L. prolificans (MIC50/MIC90 0.12/0.2µg/mL) including biofilm formation by the latter80–82. The geometric mean MICs of olorofim were significantly lower for all Scedosporium species and L. prolificans compared with those of voriconazole, posaconazole, amphotericin B, and caspofungin80. Less in vitro data are available for Fusarium species, but susceptibility appears to be species-specific, with lower MICs observed for F. proliferatum than F. solani species complex and F. dimerum83. Olorofim has no activity against the Mucorales or the dematiaceous pathogen Exophiala dermatitidis77,84.\n\nIn murine models of profound neutropenia and chronic granulomatous disease with disseminated and pulmonary aspergillosis, respectively, intraperitoneal administration of olorofim lead to significantly reduced serum GM levels and organ fungal DNA burden and improved survival as compared to controls85. In a murine model of acute sinopulmonary aspergillosis due to A. flavus, olorofim had comparable antifungal activity to posaconazole for the outcomes of decline in GM, histologic clearance of lung tissue, and survival86.\n\nPharmacokinetics/pharmacodynamics. Olorofim is available in oral and IV formulations and demonstrates time-dependent antifungal activity86,87. Olorofim initially has a fungistatic effect on Aspergillus isolates but prolonged exposure is fungicidal88. Pharmacokinetic studies in mice have identified good distribution of olorofim to tissues including the kidney, liver, and lung, with lower levels of detection in the brain77. In a phase 1 study of multiple doses of an immediate-release tablet (360mg daily for 10 days), steady state was reached within three days of dosing, and once attained, mean plasma trough levels were 1 to 2µg/mL and exceeded 0.7µg/mL in all subjects. There was evidence of enterohepatic recirculation. Olorofim was well-tolerated in all eight subjects with no serious adverse events and no subject withdrawn due to an AE. Drug-related adverse events included increased ALT (N=2), nausea and diarrhea (N=1), and dizziness (N=1)89. Olorofim is a weak inhibitor of CYP3A490.\n\nClinical development. Olorofim received designation from the U.S. FDA as a breakthrough therapy in 2019 and as an orphan drug in 2020. The European Medicines Agency Committee for Orphan Medicinal Products also granted orphan drug status to olorofim for the treatment of invasive aspergillosis and scedosporiosis in March 2019. A phase 2 clinical trial of olorofim for the treatment of IFDs due to resistant fungi including azole-resistant aspergillosis, scedosporiosis, and lomentosporiosis is ongoing (FORMULA-OLS; NCT03583164) as is a phase 1 drug-drug interaction study with itraconazole and rifampicin (NCT04171739).\n\n\nConclusion\n\nDespite significant advances in prevention, diagnostic, and management of IFDs over the past several decades, IFDs remain a formidable threat to immunocompromised hosts. Indeed, attributable mortality may still approach 90% in the most vulnerable patients infected with highly-resistant pathogens1. In addition to strategies to augment host response and reduce immunosuppression, novel therapeutics with potent fungicidal activity and low toxicity are urgently needed. We review investigational drugs in clinical phases of development, including three agents within three novel antifungal classes targeting the fungal cell wall and nucleic acid metabolism, which demonstrate early promise to combat these life-threatening infections.\n\n\nData availability\n\nNo data is associated with this article.",
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PubMed Abstract | Publisher Full Text | Free Full Text\n\nNishimoto AT, Wiederhold NP, Flowers SA, et al.: In vitro activities of the novel investigational tetrazoles VT-1161 and VT-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans. Antimicrob Agents Chemother. 2019; 63(6): e00341-19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWiederhold NP, Patterson HP, Tran BH, et al.: Fungal-specific Cyp51 inhibitor VT-1598 demonstrates in vitro activity against Candida and Cryptococcus species, endemic fungi, including Coccidioides species, Aspergillus species and Rhizopus arrhizus. J Antimicrob Chemother. 2018; 73(2): 404–408. PubMed Abstract | Publisher Full Text\n\nGarvey EP, Sharp AD, Warn PA, et al.: The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis. Med Mycol. 2020; 58(4): 505–513. PubMed Abstract | Publisher Full Text\n\nWiederhold NP, Lockhart SR, Najvar L, et al.: The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris. Antimicrob Agents Chemother. 2019; 63(3): e02233-18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShubitz LF, Trinh HT, Galgiani JN, et al.: Evaluation of VT-1161 for treatment of coccidioidomycosis in murine infection models. Antimicrob Agents Chemother. 2015; 59(12): 7249–7254. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGebremariam T, Alkhazraji S, Lin L, et al.: Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. Antimicrob Agents Chemother. 2017; 61(9): e00390-17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWiederhold NP, Shubitz LF, Najvar LK, et al.: The novel fungal Cyp51 inhibitor VT-1598 is efficacious in experimental models of central nervous system coccidioidomycosis caused by Coccidioides posadasii and Coccidioides immitis. Antimicrob Agents Chemother. 2018; 62(4): e02258-17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrand SR, Degenhardt TP, Person K, et al.: A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 2018; 218(624): 624.e1–624.e9. PubMed Abstract | Publisher Full Text\n\nElewski B, Brand S, Degenhardt T, et al.: A Phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study to evaluate the efficacy and safety of VT‐1161 oral tablets in the treatment of patients with distal and lateral subungual onychomycosis of the toenail. Br J Dermatol. 2020. PubMed Abstract | Publisher Full Text\n\nRodvold KA, George JM, Yoo L: Penetration of anti-infective agents into pulmonary epithelial lining fluid: Focus on antibacterial agents. Clin Pharmacokinet. 2011; 50(10): 637–64. PubMed Abstract | Publisher Full Text\n\nColley T, Alanio A, Kelly SL, et al.: In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection. Antimicrob Agents Chemother. 2017; 61(5): e02280-16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRudramurthy SM, Colley T, Abdolrasouli A, et al.: In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris. J Antimicrob Chemother. 2019; 74(10): 2943–2949. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHope WW, Kruhlak MJ, Lyman CA, et al.: Pathogenesis of Aspergillus fumigatus and the Kinetics of Galactomannan in an In Vitro Model of Early Invasive Pulmonary Aspergillosis: Implications for Antifungal Therapy. J Infect Dis. 2007; 195(3): 455–466. PubMed Abstract | Publisher Full Text\n\nColley T, Sehra G, Daly L, et al.: Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection. Sci Rep. 2019; 9(1): 9482. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKimura G, Nakaoki T, Colley T, et al.: In vivo biomarker analysis of the effects of intranasally dosed PC945, a novel antifungal triazole, on Aspergillus fumigatus infection in immunocompromised mice. Antimicrob Agents Chemother. 2017; 61(9): e00124-17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPagani N, Armstrong-James D, Reed A: Successful salvage therapy for fungal bronchial anastomotic infection after -lung transplantation with an inhaled triazole anti-fungal PC945. J Hear Lung Transplant. 2020; 39(12): 1505–1506. PubMed Abstract | Publisher Full Text\n\nOliver JD, Sibley GEM, Beckmann N, et al.: F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci U S A. 2016; 113(45): 12809–12814. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWiederhold NP, Najvar LK, Jaramillo R, et al.: The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis. Antimicrob Agents Chemother. 2018; 62(9): e00999-18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBuil JB, Rijs AJMM, Meis JF, et al.: In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates. J Antimicrob Chemother. 2017; 72(9): 2548–2552. PubMed Abstract | Publisher Full Text\n\nWiederhold NP, Law D, Birch M: Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro activity against Scedosporium species and Lomentospora prolificans. J Antimicrob Chemother. 2017; 72(7): 1977–1980. PubMed Abstract | Publisher Full Text\n\nBiswas C, Law D, Birch M, et al.: In vitro activity of the novel antifungal compound F901318 against Australian Scedosporium and Lomentospora fungi. Med Mycol. 2018; 56(8): 1050–1054. PubMed Abstract | Publisher Full Text\n\nKirchhoff L, Dittmer S, Weisner AK, et al.: Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans. J Antimicrob Chemother. 2020; 75(8): 2133–2140. PubMed Abstract | Publisher Full Text\n\nJorgensen KM, Astvad KMT, Hare RK, et al.: EUCAST Determination of Olorofim (F901318) Susceptibility of Mold Species, Method Validation, and MICs. Antimicrob Agents Chemother. 2018; 62(8): e00487-18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKirchhoff L, Dittmer S, Buer J, et al.: In vitro activity of olorofim (F901318) against fungi of the genus, Scedosporium and Rasamsonia as well as against Lomentospora prolificans, Exophiala dermatitidis and azole-resistant Aspergillus fumigatus. Int J Antimicrob Agents. 2020; 56(3): 106105. PubMed Abstract | Publisher Full Text\n\nSeyedmousavi S, Chang YC, Law D, et al.: Efficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease. Antimicrob Agents Chemother. 2019; 63(6): e00129-19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNegri CE, Johnson A, McEntee L, et al.: Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus. J Infect Dis. 2018; 217(7): 1118–1127. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHope WW, McEntee L, Livermore J, et al.: Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease. mBio. 2017; 8(4): e01157-17. PubMed Abstract | Publisher Full Text | Free Full Text\n\ndu Pré S, Beckmann N, Almeida MC, et al.: Effect of the Novel Antifungal Drug F901318 (Olorofim) on Growth and Viability of Aspergillus fumigatus. Antimicrob Agents Chemother. 2018; 62(8): e00231-18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKennedy T, Allen G, Steiner J, et al.: Multiple Dose Pharmacokinetics of an Immediate-Release Tablet Formulation of F901318 in Healthy Male and Female Subjects. In: European Congress of Clinical Microbiology and Infectious Diseases. Vienna, Austria; 2017; P1710. Reference Source\n\nKennedy T, Graham A, Steiner J, et al.: An open-label study in healthy volunteers to evaluate the potential for cytochrome P450 3A4 inhibition by F901318 using oral midazolam as a probe. In: European Congress of Clinical Microbiology and Infectious Diseases. Vienna, Austria; 2017; P1737. Reference Source"
}
|
[
{
"id": "89343",
"date": "23 Jul 2021",
"name": "Charalampos Antachopoulos",
"expertise": [
"Reviewer Expertise 1. Antifungal agents (in vitro activity against planktonic fungal cells or biofilms)",
"2. Host immune responses against fungal infections",
"3. Pharmacokinetics and safety of novel antimicrobial agents in pediatric patients"
],
"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 well-written and comprehensive paper summarizing recent data on novel antifungal agents in clinical development. Table 1 is very helpful. I have only few minor comments:\nAbstract: consider change “we examine” to: “we review / present / discuss”.\n\nFosmanogepix: please provide more specific in vitro data on species (rather than genera) susceptibility for Aspergillus spp, Fusarium spp and Scedosporium spp.\n\nIn vitro antifungal activity of fosmanogepix: it should be mentioned that MEC rather than MIC is determined for assessment of activity against molds.\n\n“Fosmanogepix also has activity against fungi in the order Mucorales (MIC ranges of 1 to 8 µg/mL)”: please provide reference for this statement; is the term MIC correct or should it be replaced by MEC?\n\n“Ibrexafungerp has fungistatic activity against Aspergillus species (MIC range <0.06 µg/mL to 32 µg/mL…)”: in the reference cited by the authors (ref. 25, Ghannoum et al, AAC 2018), ibrexafungerp in vitro activity against Aspergillus had been determined using both MEC and MIC; the MIC values tended to be 8-fold higher than correspondent MEC values. Please modify the text accordingly.\n\nAre there data on the in vitro activity of ibrexafungerp and rezafungin against Candida parapsilosis in comparison with other Candida species?\n\nWhat is the published evidence for PK/PD indices associated with therapeutic outcome for each one of the novel antifungal agents presented in this paper?\n\nConclusion: the content of the conclusion paragraph would fit more for an introduction rather than a wrap-up of the main findings. I suggest to significantly modify this section, in order to briefly mention the novel agents in clinical development and their selective advantages compared to our current antifungal armamentarium.\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": [
{
"c_id": "7635",
"date": "12 Jan 2022",
"name": "Samantha Jacobs",
"role": "Author Response",
"response": "Response to Reviewer #1 Comments 12.27.2021 This is a well-written and comprehensive paper summarizing recent data on novel antifungal agents in clinical development. Table 1 is very helpful. I have only few minor comments: 1. Abstract: consider change “we examine” to: “we review / present / discuss”. Author response: We have changed the wording to “We discuss…” 2. Fosmanogepix: please provide more specific in vitro data on species (rather than genera) susceptibility for Aspergillus spp, Fusarium spp and Scedosporium spp. Author response: We have specified the in vitro activity of fosmanogepix to the species level including representative MEC values. 3. In vitro antifungal activity of fosmanogepix: it should be mentioned that MEC rather than MIC is determined for assessment of activity against molds. Author response: We have added a line noting this distinction. 4. “Fosmanogepix also has activity against fungi in the order Mucorales (MIC ranges of 1 to 8 µg/mL)”: please provide reference for this statement; is the term MIC correct or should it be replaced by MEC?Author response: We have added the reference for this statement (reference #2). Indeed, the manuscript, published in 2011, used MIC rather the MEC determination for activity of fosmanogepix against R. oryzae and R. microsporus. We have also added another reference that reports MEC values (reference #3). 5. “Ibrexafungerp has fungistatic activity against Aspergillus species (MIC range <0.06 µg/mL to 32 µg/mL…)”: in the reference cited by the authors (ref. 25, Ghannoum et al, AAC 2018), ibrexafungerp in vitro activity against Aspergillus had been determined using both MEC and MIC; the MIC values tended to be 8-fold higher than correspondent MEC values. Please modify the text accordingly. Author response: Thank you for your comment. We have modified the text to report the MEC rather than MIC determinations for ibrexafungerp against Aspergillus species. 6. Are there data on the in vitro activity of ibrexafungerp and rezafungin against Candida parapsilosis in comparison with other Candida species? Author response: Thank you for your question. The in vitro activity of ibrexafungerp against C. parapsilosis is comparable or more potent than that of echinocandins. The MICs against C. parapsilosis are generally similar to those of other Candida species. For rezafungin, the in vitro activity against C. parapsilosis is less potent than against other common Candida species causing disease. These data are added to the text. 7. What is the published evidence for PK/PD indices associated with therapeutic outcome for each one of the novel antifungal agents presented in this paper? Author response: For fosmanogepix, ibrexafungerp, rezafungin, and olorofim, we have included the key PK/PD indices associated with therapeutic outcome in experimental animal models as there are insufficient clinical data to determine this information. We have also created an additional table (Table 2) to highlight this information. 8. Conclusion: the content of the conclusion paragraph would fit more for an introduction rather than a wrap-up of the main findings. I suggest to significantly modify this section, in order to briefly mention the novel agents in clinical development and their selective advantages compared to our current antifungal armamentarium. Author response: We have modified the conclusion as suggested by the reviewer to summarize and highlight the advantages of the most promising investigational agents discussed in the manuscript."
}
]
},
{
"id": "99295",
"date": "02 Dec 2021",
"name": "Shahram Mahmoudi",
"expertise": [
"Reviewer Expertise Medical Mycology",
"Antifungal Drugs"
],
"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 by Jacobs et al. summarizes the antifungal drugs in clinical trials. The corresponding author is experienced, the study is well written, and when looked alone, it seems perfect.\nHowever, I think the following points need to be considered by the authors:\nPlease be consistent in the use of units. In some cases, the unites are linked to the numbers (e.g. 35mg/L), and in the rest are separated by a space (e.g. 35 mg/L). Please add one space between numbers and units throughout the manuscript.\n\nIn my opinion, conclusion needs to be changed as in its current form it looks like the aim of study and not a conclusion.\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? No",
"responses": [
{
"c_id": "7636",
"date": "12 Jan 2022",
"name": "Samantha Jacobs",
"role": "Author Response",
"response": "Response to Reviewer #2 Comments 12.27.2021 The study by Jacobs et al. summarizes the antifungal drugs in clinical trials. The corresponding author is experienced, the study is well written, and when looked alone, it seems perfect. However, I think the following points need to be considered by the authors: Please be consistent in the use of units. In some cases, the unites are linked to the numbers (e.g. 35mg/L), and in the rest are separated by a space (e.g. 35 mg/L). Please add one space between numbers and units throughout the manuscript. Author response: We have added one space between numbers and units throughout the manuscript. In my opinion, conclusion needs to be changed as in its current form it looks like the aim of study and not a conclusion Author response: We have modified the conclusion as suggested by the reviewer to summarize and highlight the advantages of the most promising investigational agents discussed in the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/10-507
|
https://f1000research.com/articles/11-34/v1
|
12 Jan 22
|
{
"type": "Research Article",
"title": "Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats",
"authors": [
"Ricardo Aparecido Pereira",
"Albimara Hey",
"Alexandre Lustoza de Carli",
"Camila Garcia Salvador Sanches",
"Jardel Cristiano Bordion",
"Genice Iurckevicz",
"Jessica Wouk",
"Pablo Almeida",
"Luiz Augusto da Silva",
"Rozilda Penteado",
"Anaclara Prasniewski",
"Tatiane Luiza Cadorin Oldoni",
"Anayana Zago Dangui",
"Carlos Ricardo Maneck Malfatti",
"Albimara Hey",
"Alexandre Lustoza de Carli",
"Camila Garcia Salvador Sanches",
"Jardel Cristiano Bordion",
"Genice Iurckevicz",
"Jessica Wouk",
"Pablo Almeida",
"Luiz Augusto da Silva",
"Rozilda Penteado",
"Anaclara Prasniewski",
"Tatiane Luiza Cadorin Oldoni",
"Anayana Zago Dangui"
],
"abstract": "Background: Oxidative stress and the mild inflammatory process present in diabetes play a critical role in the pathogenesis of the disease and its comorbidities. This understanding has opened new avenues and targets for developing improved treatments since the risk factors associated with diabetes may be reduced through non-pharmacological interventions. In this sense, plant extracts could be efficient in preventing or assisting these pathological conditions treatment. Methods: Diabetes mellitus was induced in 24 rats, which were allocated in 4 groups: Control (CT), Control+Baccharis (CT-B), Diabetes (DB), and Diabetes+Baccharis (DB-B). For 28 days, the animals of CT-B and DB-B groups were treated, via gavage, with B. dracunculifolia extract at 50 mg.kg-1. Results: The DB group presented higher values than the DB-B group on parameters such as creatinine (26.42%), urea (31.42%), and triglycerides (60.80%). Creatinine and triglycerides values of DB-B group (0.39±0.01 e 75.0±8.4, receptively) were equivalent to the values of CT group (0.32±0.01 e 71.7±5.4) and of CT-B group (0.39±0.01, and 58.8±4.5). The treatment with B. dracunculifolia improved the levels of fasting glucose and response of glucose tolerance (32%), insulin (52,17%) and lipid peroxidation (liver 33.33%, kidney 38.77%) when compared to the DB group. Conclusions: The phenolic compounds and the anti-inflammatory activity of the extract of Baccharis dracunculifolia may be responsible for the hypoglycemic effect observed in the study.",
"keywords": [
"Medicinal plants",
"free radicals",
"antioxidants"
],
"content": "List of abbreviations\n\nALT: Alanine aminotransferase\n\nAST: Aspartate aminotransferase\n\nCT: Control\n\nCT-B: Control+Baccharis\n\nDB: Diabetes\n\nDB-B: Diabetes+Baccharis\n\nDM: Diabetes mellitus\n\nHBA1c: Glycated hemoglobin\n\nHPLC: High-Performance Liquid Chromatography\n\nOGTT: Oral glucose tolerance test\n\nROS: Reactive Oxygen Species\n\nTBARS: Thiobarbituric acid reactive substances\n\n\nIntroduction\n\nDiabetes mellitus (DM) is a public health problem, and according to the International Federation of Diabetes’ data, the number of diabetic patients is increasing. In total, 463 million cases were registered in 2019, and by 2045, 700 million cases are estimated (IDF 2019). The mechanisms involved in diabetes mellitus and hyperglycemia are complex; however, in the past few years, this pathology has been related to oxidative stress and high levels of reactive oxygen species (ROS) (Retnakaran et al. 2017). DM, in the long-term, may damage human health, cause failure or dysfunction in several organs including the eyes, nerves, heart, kidney, and blood vessels (Retnakaran et al. 2017; Elbatreek et al. 2019; Sani et al. 2019).\n\nDiabetes without the correct diagnostic and treatment may lead to death (Guo et al. 2020). Therefore, researchers are seeking new strategies for the treatment of DM, and those which involve natural products have been receiving special attention (IDF 2019; Sani et al. 2019; ADA 2020). An example of a natural product is Baccharis dracunculifolia, a plant with potent antioxidant activity, which may prevent mitochondrial oxidative damage.\n\nB. dracunculifolia, known as the rosemary-of-the-field, belongs to the Asteraceae family, and it is a shrubby, colonizer, and invasive plant. B. dracunculifolia is a medicinal plant popularly utilized because of its anti-inflammatory, anti-ulcers properties and also because of its effects against hepatic diseases. From this plant, green propolis is obtained, which is a highly efficient product against microorganisms, and much valorized in the international market (Dallaqua and Damasceno 2011; Guimarães et al. 2012; Bonin et al. 2020). B. dracunculifolia antioxidant activities were studied by Hocayen (2016), who performed extractions with different solvents (ethanol, methanol, and acetone). The results showed that all extracts have antioxidant effects, especially the one extracted with methanol solvent (Yan 2014; Halim and Halim 2019; Kaludercic and Di Lisa 2020).\n\nStudies have been relating the production of ROS with diabetes mellitus observing the fact that lipid peroxidation biomarkers increase, while endogenous antioxidant syntheses decrease (Fatani et al. 2016; Egini et al. 2017; Ghazizadeh et al. 2019; Halim e Halim 2019). Thus, a way of avoiding the harmful effects triggered by ROS is the supplementation with compounds that possess antioxidant activities. Once the antioxidants react rapidly in the organism, the damages caused by the free radicals may be delayed or even prevented (Incalza et al. 2018; ADA 2020; Wang et al. 2020). Therefore, the present study analyzed the effects of the methanolic extract of B. dracunculifolia on glucose, creatinine, urea, plasmatic transaminases, glycated hemoglobin (HbA1c) and thiobarbituric acid reactive substances (TBARs) levels, as well as histological parameters in diabetic rats.\n\n\nMethods\n\nAll the experimental procedures in this study were approved by the Institutional Ethics Committee on Animal Use (protocol no. 029/2012) of Midwest State University of Paraná, Guarapuava, Paraná, Brazil. All efforts were made to ameliorate any suffering of animals by performing the experimentation under the regulations of the Brazilian National Council for the Control of Animal Experimentation. This study is reported in line with the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines (Aparecido Pereira 2021).\n\nThis study included 24 male adult albino Wistar rats, housed in a temperature-controlled environment (22 °C ± 2 °C), with an inverted light-dark cycle (12/12 hours) and acclimated for two weeks before the study (Animal Facility of the Midwest State University of Paraná, Guarapuava, Paraná, Brazil). Potable water and a standard diet were available ad libitum throughout the experiment. The animals were allocated into four groups of 6 animals each: Control (CT), nondiabetic animals that received water, 0.75 mL/100 g as treatment; Control+Baccharis (CT-B), nondiabetic animals that received B. dracunculifolia extract at 50 mg.kg−1; Diabetes (DB), diabetic animals that received water, 0.75 mL/100 g as treatment and Diabetes+Baccharis (DB-B), diabetic animals that received B. dracunculifolia extract at 50 mg.kg−1. All treatments were daily, uninterrupted, and performed orally by gavage. For sample size calculation was used software G Power (Faul et al. 2007), based on Cohen's principles (Charan and Kantharia 2013). The groups were randomly formed using a table of random numbers. The animals were placed in identified boxes and with markings on their tails to avoid confusion (Festing 2006).\n\nAfter acclimatization, some animals were induced to an experimental model of diabetes by streptozotocin (Sigma, St. Louis, USA) was dissolved in cold citrate buffer at 0.1 M and pH 4.5. The intraperitoneal injection (IP) was performed after 12 h of fasting at a concentration of 50 mg.kg−1 (body weight) (Radenković et al. 2016). After seven days, this procedure was repeated. Fourteen days after the first application, fasting glycemic levels were estimated. Rats with fasting blood glucose (BG) values between 150 and 250 mg.dL−1 were considered diabetic and included in the study. Animals of non-diabetic groups underwent the same manipulations, being intraperitoneally injected with 0.9% saline solution, at the end of this initial phase, non-induced animals that presented glucose lower than 100 mg/dL were included in the study.\n\nSamples of the sheets of Baccharis dracunculifolia (800g) were collected at Midwest State University, CEDETEG campus in Guarapuava, Paraná, Brazil. Harvesting geographic coordinates were: 25° 23′36″ south latitude and 51° 27′19″ west longitude. This region has an altitude of approximately 1100 m, an average annual rainfall of 1711 mm, and an average annual temperature of 16.7 °C. An exsiccate of the plant was deposited at the Museu Botânico Municipal (MBM) herbarium, and registered with the number 385123.\n\nAfter harvesting, the plants were naturally dried for ten days on a clothesline in order to remove existing humidity and avoid microbiological contaminations. The methanolic extract of B. dracunculifolia was performed according to a standardized method (Hocayen et al. 2012). Firstly, the residual humidity test was performed according to the Brazilian Pharmacopoeia (2019). After, an agitation extraction method was applied. A proportion of 50g of B. dracunculifolia to 220 mL of methanol was utilized. This solution was maintained under constant stirring for one week, using the FANEM® Mod-255 kline shaker (Guarulhos, São Paulo, Brazil) at 180 revolutions per minute. Next, vacuum filtration with Kitasato was performed, and then, the filtered sample was put into a rotary evaporator RV 10 Basic® (IKA, Königswinter, Germany) to remove all methanol. The yield of the metanolic extract, cold dried (Re), was 12%. The obtained extract was diluted in Tween 80 solution and distilled water in a 1:8 proportion, aiming to improve extract solubilization and facilitate the administration, resulting in a solution of 125 mg.mL−1 concentration.\n\nThe chromatographic profile of the methanolic extract of Baccharis dracunculifolia was analyzed by high-performance liquid chromatography (HPLC). First, the samples were injected in a Varian equipment model 920-LC. A mixture of standards, described below, was subsequently injected into a C-18 Microsorb MV 100 reverse phase column (250 × 4.6 mm, 5 μm particle size). The standard flow was maintained at 1 mL min−1. The reverse-phase analysis consisted of solvent A (acidified water, 0.1% H3PO4, pH: 2.16) and solvent B (methanol). The gradient pumping system was 30% (B) at the start, 64% (B) at 15 min, 75% (B) in 26 min, 95% (B) in 28 min, returning to 30% (B) in 32 min, and remaining stable up to 40 min. The column was maintained at a constant temperature of 30 °C. The injection volume of each sample was 10 μL. The compounds were identified according to their elution order, and by comparing their retention time with those of their standard. The evaluated standards were: coumaric acid, ferulic acid, rutin, cinnamic acid, kaempferol, apigenin, galangine, pinocembrine, and quercitin (authentic analytical standards). All samples and standards were previously filtered with nylon membranes (0.45 μm pore diameter - Millipore).\n\nAt the start of the experiment, the animals were deprived of food for 12 hours to determine fasting glucose. The analysis was performed on days 0, 7, 14, and 28 of the experiment with glucose test strips and a portable glucometer (ACCU-CHEK® Active), utilizing tail vein blood.\n\nAfter 28 days of treatment with B. dracunculifolia extract, animals of all experimental groups were fasted for 12 h and were anesthetized with IP of ketamine/xylazine (80/10 mg.kg−1). After complete anesthesia, all rats were euthanized by exsanguination (cardiac puncture), an appropriate method for tissue dissection and preservation (Pierozan et al. 2017). Blood samples were collected by cardiac puncture (without and with EDTA anticoagulant) for subsequent analyses such as glycated hemoglobin (HbA1C), cholesterol, triglycerides, creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glucose levels. These biochemical parameters were analyzed utilizing specific kits by Labtest Diagnostic SA® (HbA1C Turbiquest REF. 385, Cholesterol Liquiform REF. 76, Triglycerides Liquiform REF. 87, Creatinine REF. 35, Urea UV Liquiform REF. 104, AST/GOT Liquiform REF. 109, ALT/GPT Liquiform REF. 108) and a semi-automatic spectrophotometer (Diaglobe CA-2006), and insulin levels were determined by radioimmunoassay (RIA).\n\nThe lipid peroxidation level of hepatic and renal tissues was analyzed utilizing Janero (1990) protocol, described briefly below. The degree of lipid peroxidation was measured by Thiobarbituric acid reactive substances (TBARS) assay. The organs (liver, kidneys and pancreas) tissue homogenates were added to a 10% trichloroacetic acid solution and a 0.67% thiobarbituric acid solution. After adding n-butanol, the colored supernatant was read in a spectrophotometer at 535 nm (UV Vis Spectrophotometer METROLAB 1700). A concentration curve was performed, with malondialdehyde as standard, at concentrations of 1.5, 3.0, 4.5, 6.0 and 10.0 mMol/mL. The TBARS results were expressed in mMol of TBARS/g of tissue.\n\nOral glucose tolerance test (OGTT) was performed on the 14th day of treatment. In order to perform the test, the animals were fasted for 14 hours. After fasting, a blood sample was collected from the tail vein, corresponding to time (0). Next, a glucose dosage was administrated (1 mg/kg – body weight) through gavage. Blood samples were collected at times 15, 30, and 60 min after glucose administration. Glycemia was determined by utilizing a portable glucometer (ACCU-CHEK® Active).\n\nIn order to evaluate the presence or absence of histological alterations, vital organs were collected, such as: pancreas, kidney, and liver. The samples were weighed and evaluated macroscopically concerning their shape, consistency, and color. After, the samples were placed in 10% buffered formalin solution to a subsequent preparation of histological slides. Tissues were included in paraffin blocks, cut in a microtome in slides of 3-4 micrometers, and colored by Hematoxylin-eosin technique (Cardiff et al. 2014). The mounted specimens were observed and were scored under light microscopy and the images were captured by a camera connected to an optical microscope (Olympus BX-40; Olympus, Tokyo, Japan), for a qualitative comparison of the structural changes.\n\nAll results are presented as mean ± S.D. Statistical analyses were performed in SPSS software, Windows 23.0 version (Chicago, IL, EUA). Analyses of normality were performed utilizing the Shapiro-Wilk test, followed by one-way ANOVA. Differences were considered statistically significant at p < 0.05. Post-hoc Student-Newman-Keuls was used to identify significant differences between the groups.\n\n\nResults\n\nThe results of HPLC analysis for the identification of the compounds present in the methanolic extract of B. dracunculifolia are shown in Table 1 (Aparecido Pereira 2021). Chrysin, pinocembrine, and coumaric acid were identified in the tested sample.\n\nNo clinical manifestation that could characterize the presence of another underlying disease in the animals was observed. Weekly results of capillary blood glucose, oral glucose tolerance test (OGTT), and plasmatic insulin levels may be observed in Figure 1. Capillary blood glucose levels of DB-B group animals were decreased when compared to the DB group from the 2nd week of treatment (80%, p < 0.05) (Figure 1A). After the start of treatments, no animals were excluded, all tests were performed with n = 6.\n\nData present mean ± ME (n = 24). (a,b,c) different letters are statistically different among groups (p < 0.05; Student-Newman-Keuls afer ANOVA oneway). The measurements were performed after 12 h of food fasting. CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis.\n\nIn the OGTT test, DB-B group animals presented lower levels of glucose at all times tested when compared to the DB group (32%, p < 0.05). In fasting measurements, the animals of the DB-B group did not present any significant difference compared to the CT group, but glucose levels were elevated in the 30 min (100%, p < 0.05), 60 min (200%, p < 0.05) and 150 min tests (150%, p < 0.05).\n\nThe DB-B group presented an increase in plasmatic insulin levels when compared to the DB group (52.17%, p < 0.01) (Figure 1C). Lower levels of plasmatic insulin were noticed in DB groups when compared to the CT group (200%, p < 0.001).\n\nBiochemical values may be observed in Table 2. The DB group, when compared to the DB-B group, presented higher values of creatinine (26.42%, p < 0.05), urea (31.42%, p < 0.01), and triglycerides (60.80%, p < 0.01). DB-B group creatinine’s and triglycerides’ values (0.39 ±0.01 e 75.0 ±8.4) were similar to the CT group (0.32 ± 0.01 e 71.7 ± 5.4) and CT-B (0.39 ± 0.01 e 58.8 ± 4.5).\n\n* Comparing to DB group. The measurements were performed 12 h after food fasting. n = 24. CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis; ALT – alanine aminotransferase; AST – aspartate aminotransferase.\n\nThe effects of B. dracunculifolia treatment over liver and kidney lipid peroxidation are presented in Figure 2. In the DB group, an increase of lipid peroxidation was noticed when compared to the CT group (80%; p < 0.05). The DB-B group presented a significant reduction in TBARs levels when compared to the DB group (liver 33.33% p < 0.05 and kidney 38.77%, p < 0.05), and similar levels when compared to CT group.\n\nData represent mean ± ME (n=24). a and b show statistical differences between groups (p<0.05; Student-Newman-Keuls after ANOVA oneway). CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis.\n\nDuring the experiment, diabetic animals presented characteristics corresponding to the induced disease, considering the aggressiveness of the injuries caused by the model. The effects of streptozotocin in glucose homeostasis reflect the abnormalities induced by cellular toxicity due to biochemical alterations.\n\nThe histological samples, as well as the organs’ weight, are presented in Figure 3 (liver), 4 (pancreas), and 5 (kidney), with representative images of each experimental group of the present study. In histological evaluation, the CT group presented a typical histological structure. DT group demonstrated contraction in size, characterizing a fibroplasia. The deposited conjunctive tissue promotes structural contraction, altering the organ size, which is also stimulated by the decreased number of healthy cells, hypoplasia, and cellular death characterized by cellular necrosis. The preservation of organs’ structure was observed in histological samples of the rats treated with B. dracunculifolia, being the parenchyma and stroma preserved.\n\nMicrographs of liver by the end of 28 days’ treatment. Micrographs of (A) CT; (B) CT-B; (C) DB and (D) DB-B. Optical microscope, magnification range of 400×. No use of image filters or brightness changes have been made to the images. It was observed: (A) Moderate fibroplasia with perivascular mononuclear cell inflammatory reaction associated with reactive hepatocytes; (B) Diffuse centrilobular necrosis with cytoplasmic vacuolization in hypertrophic hepatocytes, mild fibroplasia and stromal hyperemia; (C) Endothelial cells regularly distributed in vascular wall, acinar formation, hepatocytes regularly distributed and activated Kupffer cells in necrotic areas; (D) Perivascular tissue necrosis with parenchymal discrete swelling. Scale bar 25 μm. CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis.\n\nRegarding organs’ weight, during the macroscope analyses, the DB group presented higher weight and volume to kidney and liver, characterizing hypertrophy. These issues also present brighter colors on the surface, paler than the CT group. No macroscope alterations were observed in the pancreas.\n\nDifferences regarding macro-structural morphology were observed in the kidney, liver, and pancreas of DB and DB-B animals, considering the size, shape, consistency and color of the organs. As a result of the injury caused by the diabetes model, DB group organs presented microscope alterations compatible with the disease. In the liver, the development of hepatocellular intracytoplasmic vacuolation with parenchymal alterations was observed, due to lipid accumulation (Figure 3).\n\nThe DB group presented pancreatic hypotropia, islets of Langerhans, in addition to leukocyte infiltration in the acinar region and fibrosis in the remaining islets (Figure 4). In nondiabetic rats, histological structures were typical.\n\nMicrographs of pancreas by the end of 28 days’ treatment. Micrographs of (A) CT; (B) CT-B; (C) DB; and (D) DB-B. Optical microscope, magnification range of 400×. No use of image filters or brightness changes have been made to the images. It was observed: (A) Hypocellularity of Langerhans islets secreting cells with mild necrosis and hemorrhage between acinar cells; (B) Hypocellularity of acinar cells with discreet hemorrhage and Langerhans islets swelling; (C) Hypotropia of Langerhans islets with hyperplasia of acinar cells and formation of discreet inter-acinar fibroplasia; (D) Swelling and vacuolization of Langerhans islets with necrosis of secreting cells and diffuse inter-acinar necrosis associated with vacuolization. Scale bar 25 μm. CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis.\n\nIn diabetic animals, the kidneys presented alterations such as swelling, peripheral displacement of the nucleus, due to intracytoplasmic water accumulation and membrane instability, increased nucleus/cytoplasm ratio, cellular swelling, and ribosome sedimentation forming eosinophilic granules (Figure 5). The Glomerulus showed little impairment, presenting tubular and interstitial injuries (Fakhruddin et al. 2017). In the CT and CT-B groups, no alterations were found.\n\nMicrographs of kidney at the end of 28 days’ treatment. Micrographs of (A) CT; (B) CT-B; (C) DB; and (D) DB-B. Optical microscope, magnification range of 400×. No use of image filters or brightness changes have been made to the images. It was observed: (A) Necrosis of proximal contorted tubules with hydropic degeneration, and discreet glomerular cell swelling with focal hemorrhage; (B) Necrosis of proximal contorted tubules associated with glomerular sclerosis and intense hydropic degeneration in tubular epithelium; (C) Proximal contorted tubules with epithelial cell hypotrophy associated with moderate fibroplasia and glomerular hypotrophy, but with Bowman’s space; (D) Necrosis of proximal contorted tubules, swelling and glomerular hemorrhage. Scale bar 25 μm. CT – control; CT-B – control+Baccharis; DB – diabetes; DB-B – diabetes+Baccharis.\n\n\nDiscussion\n\nAfter receiving the B. dracunculifolia treatment, animals presented decreased levels of creatinine and urea. These animals also presented a qualitative improvement in kidney morphological structure when compared to the DB group. Glomerular and proximal contorted tubules structures were conserved, in which glomerular swelling was evident as well as diffuse tubular necrosis, which may be associated with a minimization of renal damage after the plant extract ingestion.\n\nIn other studies (Kim and Kim 2012; Ahangarpour et al. 2017; Momin and Yeligar 2019), which also employed medicinal plants as treatments, the authors observed a reduction in triglycerides levels. These studies suggest that the antioxidant activity of the extracts may be responsible for the results found. The reduction in triglyceride levels may be explained by the control of certain lipoprotein hydrolysis (Achi et al. 2017; Prnova et al. 2020). The administration of methanolic B. dracunculifolia extract did not promote statistical differences between groups concerning hepatic enzyme levels (AST and ALT). However, a qualitative improvement in hepatic damage was observed in the diabetic animals treated with the plant extract.\n\nAlthough the treatment with B. dracunculifolia was able to decrease fasting glucose levels and improve diabetic animals’ response to OGTT, no reduction in HbA1C levels was observed. A possible explanation of this fact is associated with the experimental model aggressiveness, which destroys part of β-pancreatic cells and reduces the sensitization of peripheric insulin receptors (Mirza and Panchal 2019). Due to this fact, after food intake, glucose levels take a longer time to return to basal levels, promoting higher glycosylation of hemoglobin in diabetic rats. Another explanation is associated with the average life of rats’ red blood cells, 120 days. Once the treatment was administrated for 28 days, there was no adequate time to cause a reduction in HbA1C levels.\n\nAfter administrating B. dracunculifolia treatment in the DB-B group, higher concentrations of plasmatic insulin were observed when compared to the DB group and according to histological analyses of liver, kidney, and pancreas samples, the animals of the DB-B group presented fewer alterations when compared to the DB group. Studies employing different types of plants demonstrated an increase of insulin excretion in experimental models of diabetes (El-Sayed et al. 2009; Achi et al. 2017; Noor et al. 2017; Effiom et al. 2019).\n\nThe DB group also showed a significant increase in lipid peroxidation when compared to the CT group. This fact may be attributed to the activation of the oxidative system triggered by the pathology, which favors oxidative stress (Sharma et al. 2019). The DB-B group presented a significant reduction in lipid peroxidation (both in the liver and kidney tissue) compared to the DB group. The animals treated with B. dracunculifolia extract also presented similar TBARs levels to nondiabetic rats (Figure 2). These results suggest that the plant has antioxidant effects in the studied organs.\n\nIn HPLC analyses performed with the methanolic extract of B. dracunculifolia used in the present work, Iurckevicz et al. (2019) identified the same compounds presented in this study results (chrysin, pinocembrine, and coumaric acid), with an addition of two compounds, caffeic acid, and ferulic acids. Studies suggest these compounds may present antioxidant and anti-inflammatory properties (Delgadillo-puga et al. 2019; Falcão et al. 2019). Salazar and collaborators (2018) also performed a chromatographic study with B. dracunculifolia and found similar results.\n\nPinocembrin, a widely studied flavonoid, is found in different products of natural origin, especially in bee propolis and in plants of the Piperaceae family (Hu et al. 2019). Scientific studies have shown that pinocembrin presents several biological properties such as anti-inflammatory, antioxidant, anticancer, and neuroprotective (Şahin and Karkar 2019; Zhang et al. 2019). Chrysin is a natural compound found in flowers, such as passion fruit and trumpet flower, and foods such as mushrooms, honey, and propolis. Studies report numerous potent activities related to this compound, such as anti-inflammatory, antioxidant, anti-allergic, anti-hypertensive, and anxiolytic (Del Fabbro et al. 2019; Veerappan, Malarvili 2019). Therefore, the presence of these compounds may contribute to the hypoglycemic effects demonstrated in the present study. Many compounds may be responsible for the antioxidant and anti-inflammatory activities of Baccharis gender, such as polyphenolics like phenolic acids, coumarins, and flavonoids (Figueiredo-Rinhel et al. 2017; Bonin et al. 2020). The results of this study suggest that the anti-inflammatory activity of B. dracunculifolia methanolic extract may be responsible for its hypoglycemic effect, which may be histologically observed by the absence of cellular necrosis and inter acinar fibroplasia, characterizing a healing process of tissue that favors the integrity of the organs.\n\n\nConclusions\n\nThe results of the present study show that the treatment with methanolic extract of B. dracunculifolia decreases lipid peroxidation levels, increases insulin rate, and improves the response in oral glucose tolerance test. It is suggested that the antioxidant activity of the plant’s extract is responsible for the improvement of diabetes mellitus. Histologically, little vascular alterations were observed, characterizing a reduction in the conditions’ typical inflammatory process. Other improvements were observed, such as vascular permeability maintenance, regulation of fibroplasia (which maintains vascular integrity), and mainly, the reduction of hydropic degeneration rate. Therefore, cellular membrane permeability and homeostasis were maintained. The study indicates that the extract of B. dracunculifolia has relevant protective properties in hepatic, renal and pancreatic tissues in vivo.\n\n\nData availability\n\nHarvard Dataverse: Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats. https://doi.org/10.7910/DVN/EXDCGC (Aparecido Pereira 2021).\n\nThis project contains the following underlying data:\n\n- Biochemical_parametric.csv\n\n- Body_weight.tab\n\n- Glucose_Evolution.tab\n\n- TBARS_organs.csv\n\n- Weight_organs.csv\n\n- Raw micrograph images\n\nHarvard Dataverse: ARRIVE checklist for ‘Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats’ https://doi.org/10.7910/DVN/EXDCGC (Aparecido Pereira 2021).\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": "164344",
"date": "03 Mar 2023",
"name": "Vijaya Anand Arumugam",
"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 “Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats”. 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 shortcomings which need to be considered. Hence, the paper can be accepted after MAJOR REVISIONS are carried out.\nComments to the author\nThe article needs a copy edit since there are some grammatical and syntax errors in the manuscript. For example, the words “of DB-B” may be as “of the DB-B”; “of CT” as “of the CT”; “of CT-B” as “of the CT-B”; “and response” as “and the response”; “, cause” as “, and cause”; “and much” as “and is much”; “who performed” as “performed”; “induced to” as “induced into”; “Oral” as “An oral”; “were fasted” as “fasted or have fasted”; “as: pancreas” as “as the pancreas”; “in 10%” as “in a 10%”; “Hematoxylin-eosin” as “The hematoxylin-eosin”; “dracunculifolia are” as “dracunculifolia is”; “, all tests” as “, and all tests”; “increase of” as “increase in”; “to CT” as “to the CT”; “a fibroplasia” as “fibroplasia”; “of liver” as “of the liver”; “in vascular” as “in the vascular”; “to kidney” as “to the kidney”; “of pancreas” as “of the pancreas”; “increase of” as “increase in”; “of kidney” as “of the kidney”; “in tubular” as “in thetubular”. The grammar mistakes which are not mentioned here are also to be checked and corrected properly.\n\nThere are some typing mistakes as well, and authors are advised to carefully proof-read the text. For example, the words “Diabetes'” may be as “Diabetes”; “diagnostic and” as “diagnosis and”; “the damages” as “the damage”; “metanolic” as “methanolic”; “reverse phase” as “reverse-phase”; “afer” as “after”; “Figure 3 (liver), 4 (pancreas), and 5” as “Figures 3 (liver), 4 (pancreas), and 5”; “days'” as “days”; “theDBgroup” as “the DB group”; “tubules structures” as “tubule structures”; “triglycerides” as “triglyceride”; “nondiabetic” as “non-diabetic”; “pinocembrine” as “pinocembrin”; “Delgadillo-puga” as “Delgadillo-Puga”; “tolerance test.” as “tolerance tests.”. The typos not mentioned here are also to be checked and corrected properly.\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, Control (CT), Diabetes mellitus (DM), Thiobarbituric acid reactive substances (TBARS), blood glucose (BG), 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 in both the abstract and in the remaining part of the manuscript and it should be followed by only the first letter of the genus (For example, Baccharis dracunculifolia when the first time appear and followed by B. dracunculifolia).\n\nIn abstract, the authors have mentioned the induction of diabetes in general and it should be rewritten with the toxin used to induce the same for better understanding.\n\nIn introduction, the authors should cite recent prevalence or incidence data since they cited only 2019 and it should be at least of 2022.\n\nThe technical terms (Latin Phrase) “in vivo (in page 3, under the heading Ethical considerations)” should be italic and it should be checked all over the manuscript.\n\nThe age group of the animals should be included in the materials and methods under the heading “Study design”. The standard diet used in the present investigation should also be included with its composition and source of the same.\n\nWhen referring to SPSS versions beginning from 19, authors should cite ‘IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, N.Y., USA)'.\n\nIn the results the images given for histopathological study should be marked properly about the changes observed in each group used.\n\nThe authors may improve the discussion of their review by focusing on the present findings and introducing data from other authors who also worked with the same or other studies with recent references.\n\nThe limitation of the present investigation may be given along with conclusion or under separate heading for understanding the concepts clearly.\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": []
},
{
"id": "175220",
"date": "12 Jun 2023",
"name": "Shahzad Irfan",
"expertise": [
"Reviewer Expertise Endocrinology",
"Animal Models",
"In-vivo experimentation",
"Medicinal chemistry."
],
"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 \"Sub-chronic effects of Baccharis dracunculifolia treatment on biochemical, oxidative, and histopathological parameters in diabetic rats\" submitted by Pereira RA et al, evaluated the extract of a medicinal plant from Asteraceae family on streptozotocin treatment adult rats. This is a good study examining the effects of traditional medicinal plants on rodent models. I have a few concerns though.\nThe authors are using the terminology diabetic rats which is incorrect. Chemically induced diabetes usually mimic type 1 diabetes. And to successfully induce type 2 diabetes high fat/high carb diets along with alloxan/streptozotocin in combination with nicotinamide treatments are used. To avoid all that confusion about the exact type of diabetes, the much better option is to mention the current state of the animal after streptozotocin which in the current case is simple hyperglycemic rats.\n\nThe title is not informative and does not suggest any study outcome/result. Please revise the title with more clarity about the outcome of the study. As the current title is unjustified for the excellent experimentation conducted in this study.\n\nIn the conclusion section, the authors mentioned insulin concentration as insulin rate and this is incorrect. As the insulin level seems to be significantly increased in the DB-B group as compared to the DB group. Whether this increase is due to the increased insulin synthesis or secretion should be investigated further.\n\nThe statistical significance of the figures has been depicted by alphabets, however, the current most accepted manner is the placement of a different number of asterisks according to the level of significance. Please review the use of alphabets on graphs.\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": "172893",
"date": "14 Jul 2023",
"name": "Franklyn Nonso Iheagwam",
"expertise": [
"Reviewer Expertise Antidiabetic Mechanisms",
"Molecular Toxicology",
"Medicinal Plants",
"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 by Pereira et al. showed Sub-chronic Baccharis dracunculifolia treatment was able to improve some biochemical, oxidative and histological parameters in streptozotocin-induced diabetic rats. Despite the reported findings, my major concern was the lack of assessment of blood glucose levels using a biochemical diagnostic kit in addition to the strip method. There are also a lot of typographical and lexical errors which need to be corrected. Below are some minor queries on the manuscript\nABSTRACT\nBackground: The background section is on oxidative stress and mild inflammatory process alone. It should also focus on diabetes as this is the background of this study.\nMethods: The parameters that were investigated should be included\nResults: “The treatment with B. dracunculifolia…” Recast this for clarity to know if it covers DB-B and CT-B or anyone. Conclusions should be restricted to what was done and observed in the study.\nINTRODUCTION\nThe research problem is focused on oxidative stress alone contrary to the aim of the study which focused on diabetes. This is further observed in the pharmacological activity of B. dracunculifolia reported in the introduction. The introduction should be improved to showcase the aim and justification of this study.\nThe reference Halim e Halim 2019 should be correctly inserted.\nMETHODS\nWhat were the animals’ age?\nWere the biochemical assessments done on EDTA or non-EDTA collected blood?\nFor the RIA, kindly state the analyser that was used and the RIA kit for reproducibility.\nRESULTS\nThe table and figure captions must be recast to confer the information they present/depict in order to stand alone.\nFigures with different parts (a, b, c etc) should be referenced in the text\n\nFor the OGTT test, kindly recast the comparison of DB-B and DB as it was not 32% all through the time range.\nThe comparison of means between DB-B and CT groups in the text has no SI unit attached to the values. What does “e” stand for? In Table 2 no comparison was made between CT and CT-B\nIn Table 1 footnotes explaining what RT and RE should be indicated\nIn Figures 1 and 2, n=6 not 24. Also, “Student-Newman-Keuls after ANOVA oneway). The measurements were performed after 12 h of food fasting” should not be included in the footnotes.\nIn Figures 3, 4 and 5, the histological changes observed in the tissues should be indicated on the histological plates Figure 3 (liver),4 …. should be Figures 3…..\nDISCUSSION\nThis section should be reported sequentially, similar to the result section. It should also be improved as it is not robust enough. Results should not be repeated in this section.\nThe conclusion indicates findings that were not synonymous with the study such as the histology and antioxidant activity. The conclusion should be hinged solely on the results of the study. Limitations should be included as well.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "175219",
"date": "14 Jul 2023",
"name": "Yulia Yusrini Djabir",
"expertise": [
"Reviewer Expertise Pharmacology"
],
"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 manuscript presents a great work of research done by the authors. It focuses on investigating the pharmacological effect of Baccharis dracunculifolia extract on diabetic rats. In overall, the methods used are sounding but some details need clarification.\nThe manuscript has been written in good English, but it probably need to be polished using a language editor to strengthen the writing style.\nTitle\nSuggested title: Baccharis dracunculifolia extract treatment Improves biochemical, oxidative, and histopathological parameters in diabetic rats\nAbstract\nThe background of the abstract has explained how oxidative stress related to DM pathophysiology. However, it requires more information about Baccharis dracunculifolia potential benefits on DM. I suggest to reduce the general information about DM and start introducing Baccharis dracunculifolia potential roles.\n\nThe aim of the study should be mentioned in the background\n\nIn the method of the abstract, the method of DM induction in the rats should be mentioned\n\nThe conclusion stated that the phenolic compound and anti-inflammatory activity of the extract may be responsible for its hypoglycaemic effect. However, the result and method did not mentioned anything about phenolic compound and anti-inflammatory activity. The conclusion in the abstract should be a brief statement of the data that are displayed in the results.\n\nIntroduction\nThe authors has provided information background that lead to the research purpose. However, information about Baccharis dracunculifolia based on recent literatures are still lacking. It may need to cite more references about Baccharis dracunculifolia. Also in the last sentence, the purpose of this study should be reformulated to cover all the parameters of interest instead of stating them one by one.\nMethods\nThe study only uses one type of dose of the extract. How the dose was chosen need to be explained in the method. Is there any pilot study to confirm the effective dose for DM?\nAt the starting point (day 0), the measurement of glucose level was performed using a portable glucometer (ACCU-CHEK® Active), it is important to check the accuracy of this device, since the baseline data is highly important as the comparison to end result following treatments. It is great that at the endpoint, the measurement was done using a semi-automatic spectrophotometer, which is a more accurate instrument.\nFor lipid peroxidation measurement, the incubation time in a specific temperature should be mentioned prior to measurement. Usually to measure MDA level using a TBARS, a certain incubation time and temperature is required.\nResult\nThe result should elaborate the interpretation of the data found without citing the references. There is one citation at the last paragraph of the result.\nIt will be better if the photomicrographs are displayed with arrows or marks to point the histopathological changes in each photo.\nIn histopathological evaluation of the liver (Figure 3), The figure legend shows that the non-diabetic control (CT) group showed a presence of fibroplasia and inflammatory reaction (A) and in treatment of Baccharis dracunculifolia in non-diabetic rats (CT-B) apparently causes centrilobular necrosis. Supposedly these results should be further explained, especially why the controls also experience moderate histopathological changes, and how these changes compared to the diabetic rats with or without extract treatment.\nIf the extract causes centrilobular necrosis in the non-diabetic rats, is this mean that the extract is not safe for use?\nSimilarly, in figure 4, according to the figure legend, even the non-diabetic control showed abnormal structure such as Hypocellularity of Langerhans islets secreting cells with mild necrosis and haemorrhage between acinar cells. More explanation is required to address this.\nin Figure 5, all groups also present abnormal structures (necrosis and hypertrophy) of renal histology. Again, this should be address in discussion\nDiscussion\nPlease also discuss the abnormality found in the histology of liver, pancreas and kidneys in CT and CT-B animals.\nConclusion\n“Histologically, little vascular alterations were observed, characterizing a reduction in the conditions’ typical inflammatory process. Other improvements were observed, such as vascular permeability maintenance, regulation of fibroplasia (which maintains vascular integrity), and mainly, the reduction of hydropic degeneration rate”\nHowever, these features have not been specifically mentioned in the discussion before. The conclusion should be consistent with result and discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? 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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-34
|
https://f1000research.com/articles/11-32/v1
|
12 Jan 22
|
{
"type": "Research Article",
"title": "The paradox of food production, consumption, poverty and malnutrition in Tanzania: an ecological study design",
"authors": [
"Novatus Tesha",
"Malale Tungu",
"Alphoncina Kagaigai",
"Boniface Yohana",
"Hevenlight A. Paulo",
"Malale Tungu",
"Alphoncina Kagaigai",
"Boniface Yohana",
"Hevenlight A. Paulo"
],
"abstract": "Background: There have been claims amongst nutrition stakeholders in Tanzania that the food basket regions, are the regions most affected by stunting among children. However, this study could not find evidence that combines food production and stunting levels, to substantiate this claim. Therefore, this study aims to compare data on stunting, food production and consumption within administrative regions of the Tanzania mainland. Methods: The study used an ecological study design to show the relationship between stunting, poverty, food production and consumption across administrative regions in Tanzania. The study used data from three national wide surveys: 2017/2018 Household Budget Survey (HBS), Tanzania National Nutrition Survey (TNNS) 2018 and Agriculture Statistics for Food Security report 2018/2019. Results: The study showed that there is a positive relationship between the prevalence of stunting and food production (r=0.43, p=0.03), while there is a negative relationship between stunting and the level of both the average monthly household consumption expenditure (r = -0.48, p = 0.01) and average monthly household food consumption expenditure (r = -0.509, p = 0.01). It was further found that some regions which have higher levels of stunting such as Njombe, have the lowest level of basic need poverty. Conclusion: The study found a positive relationship between food production and the prevalence of stunting using data across regions in mainland Tanzania. This is an indication that regional food security may not entail nutrition security, hence a call for more advocacy on nutrition-sensitive agriculture.",
"keywords": [
"Stunting",
"Food Production",
"Basic Need Poverty and Household Consumption"
],
"content": "Introduction\n\nStunting, defined as being too short for one’s age, is among the important indicators to track children’s malnutrition.1 Globally, the number of stunted children is decreasing, however, its prevalence level is still unacceptable. In the past 18 years, the number of stunted children globally, decreased by 49.2 million. It has been reported that in 2018, over 149 million (21.9%) children were estimated to have stunted growth globally, compared to 198.2 million children in 2000.2 Most of the stunted children live in developing countries, especially in Asia and Africa with 55% and 39% of children suffering from stunting, respectively. Africa is the only region where the number of cases is increasing; rising from 50.3 million in 2000 to 58.8 million in 2018 with disparities existing at the sub-national level.2,3\n\nThe prevalence of stunting in Tanzania decreased by 18% from the 1990s, from 50% of children to 32% in 2018.4 This rapid change was due to the different strategies taken by the government, in collaboration with development partners, including implementation of the National Nutrition Strategy 2011/2012 to 2015/20165 and the National Multi-Sectoral Nutrition Action Plan 2016 – 2021.6 However, this level is still high as per the World Health Organization (WHO) recommended thresholds (>= 30%). WHO defines levels of stunting in four levels: low (<20%); Medium (20 – 29%), High (30 – 39%) and very high (>=40).13,14 Despite the decrease in the prevalence level, the number of stunted children is increasing. It increased from 2.5 million in 2005 to 3 million in 2018.7 The disparity exists across regions in Tanzania Mainland. Out of 26 regions, 15 regions have a stunting prevalence of above 30%, among them, six regions have above 40%. The regions with the highest stunting levels are Njombe (53%), Rukwa (47.9%), Iringa (47.1%), Songwe (43.3), Kigoma (42.2) and Ruvuma 41%.8\n\nThe reviewed literature has shown that under-five stunting can be explained by different immediate and intermediate factors. Some of the factors include income levels, family size, education level of the mother, sex of the baby, age of the baby, feeding practices, food preparations, overall health status, types of occupation of the mother, weight of the baby and age of the mother at birth.9–12 The underlying factors of stunting are government policies, pricing of food, access to social services, farming practices and economic status of the household.6 Household poverty level and other factors related to poverty are also cited as determinates of stunting at household levels.11,12,14\n\nIn Tanzania, some regions that are leading in food production and with a small prevalence of poverty, are also leading in the prevalence of stunting. For example, Njombe has the highest level of stunting (53%) and yet, it is the region with the third lowest rate of poverty (13.2%), just above are Dar es Salaam and Kilimanjaro with 8% and 10% levels respectively.4,15 Similarly, in 2018, Ruvuma was the highest region in terms of food production but it had a stunning level of 41%. There has been a debate amongst nutrition stakeholders (those working in the government, United Nations Agencies and donor countries supporting nutrition interventions, academia and non-governmental organization in nutrition), on the controversy on regions with both high food production and stunting levels. However, to the best of our knowledge, we have not found previous research conducted to investigate this. Therefore, this study aims to compare data on stunting, food production and consumption across administrative regions of Tanzania.\n\n\nMethods\n\nThis is an ecological study design using secondary data compiled from three sources: Tanzania Household Budget Survey (HBS) 2017/2018,15 Tanzania National Nutrition Survey (TNNS) 20184 and Agriculture Statistics for Food Security report 2018/2019.16 Both HBS and TNNS are national-wise cross-sectional data organized by the Ministry of Finance and Planning and Ministry of Health respectively, while Agriculture Statistics for Food Security report 2018/2019 was prepared by the Ministry of Agriculture.\n\nData for this study was sourced from 26 Tanzania mainland administrative regions. The regions were chosen because currently, aggregated data are representative at the regional level. Similarly, regions were chosen to determine whether food production could be a determinant of stunting at the regional level and hence answering the paradox.\n\nThe 2017/18 HBS had a sample of 9,552 individuals, which allowed disintegration of the results at the regional level. The data set adopted a two-stage cluster sample design. The first stage involved the selection of enumeration areas, Primary Sampling Units, (PSUs) from the 2012 Population and Housing Census Frame.15 The second stage involved systematic sampling of households from the updated PSUs list. All household members, regardless of their age, who were the usual members of the selected households and all the visitors who were present in the household on the night before the survey, were eligible.\n\nTNNS used two-stage cluster sampling using Probability Proportional to Size (PPS), a representative at the regional and national level. The first stage sample of clusters was drawn independently for each domain. The second stage of sampling consisted of selecting households within each selected cluster, by using a systematic random selection procedure. Data were collected from the sample of 17,524 children aged 0-59 months and 9,426 women aged 15-49 years old.\n\nThe outcome variable of this study is the regional prevalence of stunting. Children were reported to be stunted if their height-for-age is more than two standard deviations below the World Health Organization’s Child Growth Standards median.16 The exposure variables were the regional food production (cereal and non-cereals food crops in metric tons), the proportion of basic need poverty, monthly household average consumption expenditure and average monthly household food consumption expenditure.\n\nData were cleaned and analyzed using Microsoft Excel and STATA version 15. Mean and standard divisions were used to summarize the numerical variables. Correlation coefficients and scatter plots were used to determine the linear relationship between outcome (regional prevalence of stunting) and exposure variables (food production, average monthly food consumption expenditure, average household monthly consumption expenditure and proportion of regional basic need poverty). Findings were presented using tables, figures and narrations. The significance level was set at 5%.\n\n\nResults\n\nThe overall prevalence of stunting for the Tanzania mainland is 33.5%, ranging from 20% in Kilimanjaro to 53.6% in the Njombe region. Basic need poverty stands at 27.5%, ranging from 8% in Dar es Salaam to 45% in the Rukwa region. On the other hand, the average food production is 977,544.80 Metric tons per year and the mean average monthly household consumption expenditure in Tanzania shilling is 399,439 ranging from 268,041 in Rukwa Region to 720,946 in Dar es Salaam and the mean average monthly household food consumption expenditure is 47,986 ranging from 34,354 in Kigoma to 70,966 in Dar es Salaam (see Table 1).\n\nComparison of basic needs poverty, food production and average monthly household consumption among regions with highest prevalence of stunting\n\nFour regions in Tanzania that have stunting above 40%4 are in the top six regions that produce the highest levels of food in the country.16 The region which is the first in food production in the country being among them16; Rukwa and Kigoma are only two regions with the highest levels of poverty15 which have also higher levels of stunting.4 However, there was no region with the highest levels of household monthly consumption expenditure15 in the top regions with highest levels of stunting.4 Furthermore, half of the regions with the highest monthly household consumption expenditure,15 have the lowest prevalence of stunting.4 It is only Lindi that has the lowest level of stunting4 and the lowest level of monthly household consumption expenditure.15\n\nThere is a significant positive linear relationship between the prevalence of stunting and the level of food production (r = 0.43, p = 0.03) i.e. the higher the level of food production the higher is the prevalence of stunting (Figure 1).\n\nThe result indicated that there is a significant negative relationship between the prevalence of stunting and the average monthly consumption expenditure levels per household per month (r = -0.48, p = 0.01) i.e. the higher the average monthly household consumption expenditure, the higher is the prevalence of stunting (see Figure 2).\n\nStunting and average monthly household food consumption expenditure\n\nIt was observed that there is a negative relationship between average monthly household food consumption expenditure and prevalence of stunting (r = -0.509, p = 0.01) (see Figure 3).\n\nThe relationship between stunting and basic needs poverty indicated that Njombe, which is the region with the highest level of stunting in the country (53%), is the region with the third lowest level of poverty (13.2%), next to Kilimanjaro (8%) and Dar es Salaam (10.5%). The prevalence of basic need poverty in Njombe, Iringa and Songwe, with stunting levels above 40%, is lower compared to other regions. However, the level of poverty and stunting in Rukwaa and Geita do not show notable differences (see Figure 4). This trend is also observed for the regions with the lowest levels of stunting which are Kilimanjaro, Dar es Salama and Morogoro (Figure 5).\n\n\nDiscussion\n\nFindings show that regions with the highest food production had a high prevalence of stunting. This result concurs with the study done in Bukombe, Tanzania, which found that children from very low income households were more likely to be stunted compared to other occupations.17 This might be true because food-producing regions entail a great deal work, often done by mothers in their small scale farms, and hence little time is given for them to take care of and feed, their children. This indicates that food security may not entail nutrition security. This may mean that very low income households spend the majority of their time on the farm, producing and consuming one type of food and are thus severely affected by seasonal household food security. Low income households may be food secure in the harvest season and food insecure in other seasons of the year while other occupations’ household may buy their food and hence have more food diversity.17,18 However, these findings contrast other studies that have found households with food insecurity and small cultivation size, were more affected by stunting, compared to those who are food secure and those with large cultivated areas.9,19\n\nOur study found that some regions like Njombe, which are among the regions with the lowest levels of poverty, have higher levels of stunting. The findings are contrary to several studies done on the determinants of stunting in developing countries across the globe, which shows that poverty is positively associated with stunting.9–11,20 The reason for this might be that mothers in regions like Njombe, are involved in several economic activities to earn their income.17 Due to this, they may have limited time with their children.17,18 In addition, labour laws in Tanzania, gives women only about three months’ maternity leave.21 Therefore, due to mothers works in the farms or as employee in the govermenent or private institurions they do not have enough time to breastfed their children, take them to hospitals and feed them accordingly.17,18\n\nIn addition, the results of the study show that regions with higher monthly household consumption expenditure, had lower levels of stunting. This means that higher consumption means increased purchasing of a variety of foods, which reduces malnutrition. This finding concurs with a study done in Tanzania, which showed that families which were not dependent on farming their own food, bought a variety of food for their families, unlike those which produce their food.17\n\n\nConclusion and Recommendations\n\nThere has been the claim that higher food production regions in Tanzania paradoxically have a higher prevalence of stunting. However, no study was previously found to substantiate this at a national level. This study has found that the more the region produces food, the more likely it is to have higher levels of stunting. In addition, it has found that some regions with the lowest levels of poverty have higher levels of stunting. However, regions with higher monthly household consumption expenditure do not have higher levels of stunting. Therefore, this indicates that food production and a lower level of poverty, might not lead to nutrition security. This study provides a picture of the relationship between food production; consumption, poverty and stunting. However, it is based on secondary data aggregated from different sources. Therefore, it provides the foundation for further studies in this area. Similarly, this information can enlighten policymakers on rethinking how to make agriculture nutrition-sensitive, so that Tanzania can attain the Sustainable Development Goals (SDGs) goal of ending malnutrition in all its forms.22\n\nThis study faced a few limitations, one of them being that the study used secondary data of which some of the variables were missing, limiting our analysis. Furthermore, data were aggregated at the regional level rather than individual level, which limited the interpretation of factors associated with malnutrition.\n\n\nData availability\n\nDryad: The Paradox of Food Production, Consumption, Poverty and Malnutrition in Tanzania\n\nhttps://doi.org/10.5061/dryad.gxd2547n9\n\nThis project contains the following underlying data:\n\n• Data_for_Regional_Stunting__Food_Production__Consumption_and_Poverty_Levels_-_Tanzania.xls\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nWe would like to thank the Ministry of Finance and Planning, Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC) and the Ministry of Agriculture for conducting the surveys and reports, which are available online for further use.\n\n\nReferences\n\nWorld Health Organization: Global nutrition targets 2025: Stunting policy brief. World Health Organization; 2014.\n\nMicha R, Mannar V, Afshin A, et al.: Global nutrition report: action on equity to end malnutrition.2020.\n\nWorld Health Organization: UNICEF/WHO/The World Bank Group joint child malnutrition estimates: levels and trends in child malnutrition: key findings of the 2020 edition.\n\nMinistry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC) [Tanzania Mainland], Ministry of Health (MoH) [Zanzibar], Tanzania Food and Nutrition Centre (TFNC), National Bu- reau of Statistics (NBS), Office of the Chief Government Statistician (OCGS) [Zanzibar] and UNICEF: Tanzania National Nutrition Survey using SMART Methodology (TNNS) 2018 Summary of the Findings. Dar es Salaam, Tanzania: MoHCDGEC, MoH, TFNC, NBS, OCGS, and UNICEF; 2018.\n\nMinistry of Health and Social Welfare: National Nutrition Strategy 201/12-2015/16.2011.\n\nUnited Republic of Tanzania: National Multisectoral Nutrition Action Plan (NMNAP) for the period July 2016 – June 2021.2016.\n\nPrime Minister’s Office (PMO), Tanzania Food and Nutrition Centre (TFNC) and UNICEF: Mid-Term Review of the National Multisectoral Nutrition Action Plan 2016-21. Dar es Salaam, Tanzania: PMO, TFNC and UNICEF; 2019.\n\nMinistry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC) [Tanzania Mainland], Ministry of Health (MoH) [Zanzibar], Tanzania Food and Nutrition Centre (TFNC), National Bu- reau of Statistics (NBS), Office of the Chief Government Statistician (OCGS) [Zanzibar] and UNICEF: Tanzania National Nutrition Survey using SMART Methodology (TNNS) 2018. Dar es Salaam, Tanzania: MoHCDGEC, MoH, TFNC, NBS, OCGS, and UNICEF; 2018.\n\nAdhikari RP, Shrestha ML, Acharya A, et al.: Determinants of stunting among children aged 0-59 months in Nepal: Findings from Nepal Demographic and health Survey, 2006, 2011, and 2016. BMC Nutr. 2019; 5(1): 1–10. Publisher Full Text\n\nAdekanmbi VT, Kayode GA, Uthman OA: Individual and contextual factors associated with childhood stunting in Nigeria: A multilevel analysis. Matern Child Nutr. 2013; 9(2): 244–259. PubMed Abstract | Publisher Full Text\n\nSunguya BF, Zhu S, Mpembeni R, et al.: Trends in prevalence and determinants of stunting in Tanzania: An analysis of Tanzania demographic health surveys (1991-2016). Nutr J. 2019; 18(1): 1–13. Publisher Full Text\n\nSemali IA, Tengia-Kessy A, Mmbaga EJ, Leyna G: Prevalence and determinants of stunting in under-five children in central Tanzania: Remaining threats to achieving Millennium Development Goal 4. BMC Public Health. 2015; 15(1): 1153. Publisher Full Text\n\nCorreia LL, AC ES, Sales Campos J, et al.: Prevalence and determinants of child undernutrition and stunting in semiarid region of Brazil. Rev Saude Publica. 2014; 48(1): 19–28. PubMed Abstract | Publisher Full Text\n\nChirande L, Charwe D, Mbwana H, et al.: Determinants of stunting and severe stunting among under-fives in Tanzania: Evidence from the 2010 cross-sectional household survey. BMC Pediatr. 2015; 15(1): 165. Publisher Full Text\n\nMinistry of Finance and Planning - Poverty Eradication Division (MoFP- PED) [Tanzania Mainland] and National Bureau of Statistics (NBS): Tanzania Mainland Household Budget Survey 2017-18. Dodoma, Tanzania: Key Indicators Report; 2019.\n\nDe Onis M, Borghi E, Arimond M, et al.: Prevalence thresholds for wasting, overweight and stunting in children under 5 years. Public Health Nutr. 2019; 22(1): 175–179. PubMed Abstract | Publisher Full Text\n\nShilugu LL, Sunguya BF: Stunting in the Context of Plenty: Unprecedented Magnitudes Among Children of Peasant's Households in Bukombe, Tanzania. Frontiers in nutrition. 2019; 7(6): 168.\n\nNordang S, Shoo T, Holmboe-Ottesen G, et al.: Women’s work in farming, child feeding practices and nutritional status among under-five children in rural Rukwa, Tanzania. British Journal of Nutrition. 2015; 114: 1594–1603. PubMed Abstract | Publisher Full Text\n\nMbwana HA, Kinabo J, Lambert C, et al.: Factors influencing stunting among children in rural Tanzania: an agro-climatic zone perspective. Food Secur. 2017; 9(6): 1157–1171. Publisher Full Text\n\nLeal VS, Lira PI, Menezes RC, et al.: Factors associated with the decline in stunting among children and adolescents in Pernambuco. Northeastern Brazil. Revista de saude publica. 2012; 46(2): 234–241. Publisher Full Text\n\nUnited Republic of Tanzania: Employment and Labour Act: 2006. PubMed Abstract\n\nAbila S: An Analyses of Threats to the Realisation of the United Nations' Sustainable Development Goals Report 2019 in the Light of the Recent Report of the Global Futures (ie the World Wildlife Fund) on the Unfolding Trends on the Environment in Nigeria and the Globe-A Call for Sustained Global Action. JL Pol'y & Globalization. 2020; 95: 38."
}
|
[
{
"id": "123223",
"date": "14 Mar 2022",
"name": "Joyce Kinabo",
"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\nCommendation: I would like to commend the authors for coming up with this paper in which they have attempted to provide some answers about the paradox relationship between food production, stunting, expenditure, and poverty in Tanzania. They have correctly pointed out that high food producing regions are also leading in the prevalence of stunting.\nSuggestion: change the title to read “the paradox of food production, expenditure, poverty, and stunting in Tanzania….” To reflect what is described in the paper.\nMethodology:\nSampling procedure for the Household Budget Survey and Tanzania National Nutrition Survey has been described but not for the agriculture statistics. The authors should explain how the data on agriculture production is collected. It would also be useful to indicate when these various surveys were carried out (date and month). This information has implications on the relationships of the variables and therefore interpretation of the results.\n\nProvide the definition of average consumption. The household budget survey presents proportion of food and non-food expenditures, it would be more logical to look into these categories and assess how they relate to stunting instead of just looking at the average expenditure and expenditure on food only. In addition, what are the kinds of foods that are accessed by households? Do they add to the diversity of nutritious foods?\nResults:\nAdd lines of fit on the correlation graphs (scatter plots) to assist the reader to get a clear picture of the relationship between the variables.\n\nStunting and average monthly household consumption expenditure (AMHCE): the authors have stated that there was a significant negative relationship between stunting and AMHCE; but explained that as AMCHE increased, stunting also increased. Is this the meaning of a negative relationship? This area needs clarification.\n\nStunting and AMHFCE: authors observed a negative relationship, but did not elaborate further on this relationship the way they have done for other relationships. There is a need for consistency.\n\nStunting and basic need poverty: what is the basis of selecting only eight regions. It is better to present data for all regions to give the reader a full perspective of the data you have analysed and single out the eight regions in the description of the results. In the current analysis, the Njombe region should appear in both figures 4 and 5. However, it would also be interesting to identify regions that appear in both figures 4&5.\n\nIt would also be more informative to present data on the relationship between stunting and monthly food and non food expenditures to show how the two types of expenditure contribute to stunting. Nevertheless, this is not a very strong indicator since it does not tell us what types of foods are purchased and consumed by children.\nDiscussion\n“This indicates that food security may not entail nutrition security” This is a statement in the discussion, but not explained fully. Authors should be cautious when using these terminologies. In this particular study, they assessed the relationship between food production or availability and stunting and not food security, which has four pillars. It would be better to say that food availability may not entail food consumption and related outcomes; rather than using words such as food and nutrition security, which were not assessed in this study.\n\nPage 7 para 3 is more speculative and not supported by the available data. It should be revised to provide more information about expenditure and what kinds of foods are purchased and actually fed to children. It would also be more logical to consider other variables such as minimum acceptable diet (MAD) for children and household dietary diversity score (HDDS).\n\nConclusion:\nThe authors have not been able to explain the paradox. The conclusion is the same as introduction. It was expected to get an explanation about the paradox and how that can be corrected.\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": []
},
{
"id": "144313",
"date": "10 Aug 2022",
"name": "Nahomi Imaeda",
"expertise": [
"Reviewer Expertise public health",
"dietary surveys",
"nutritional 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\nDespite the need for epidemiological studies targeting developing countries, there are still few publications. In this context, an ecological study design that allows low-cost analysis would be beneficial. I read this paper with great interest.\nEcological studies cannot prove causality, but the author should choose appropriate parameters to clarify the relationship with the prevalence of stunting. The author describes it as a paradox that the food production value is positively correlated with stunting, but the indicators observed are not appropriate. The author should observe in more detail what food groups are produced. For example, the production of coffee beans would not be directly related to an increase in nutrient intake.\nFurthermore, for mothers in Region Njombe, the author should show statistical data on longer hours of work in comparison with other areas.\nIn Figures 1-3:\nThe graphs presenting the 26 regions should show approximate equations. In addition, for those regions that had large residuals from the equation, the reasons should be discussed.\n\nThe figures should be drawn squares with numbers like [1], [2] - [26], indicating the name of the region, rather than a square black box, so that the stunting situation and economic situation in Tanzania can be understood.\nSince most of the readers have unknown area names in Tanzania, I suppose that as possible as simple maps should be shown with transport infrastructure (road network or ocean ports). In this peer review, I was able to get some Tanzania information by the administrative regions of Tanzania map (referred Tanzania National Nutrition Survey 2018.pdf, page 7, Figure 1), or the Tanzania transport map (website: https://www.tanzaniainvest.com/transport ). The figures of present paper did not provide enough information about regions in Tanzania.\nIn Figures 4 and 5, only 8 regions were observed, so the explanation is not sufficient.\nThe keyword “basic needs poverty” should be changed to “basic human needs” and “poverty”? or “basic needs poverty line”? And according to the PubMed Mesh, the keyword \"stunting\" is included in Growth Disorders. I recommend you refer to the PubMed Mesh to increase the number of web-search hits.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/11-32
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https://f1000research.com/articles/11-28/v1
|
11 Jan 22
|
{
"type": "Brief Report",
"title": "Foundation in Law students’ reading awareness of the case law genre",
"authors": [
"Suhaila Abdullah",
"Sareen Kaur Bhar",
"Sareen Kaur Bhar"
],
"abstract": "Background: A text of different genre might pose a different problem to students and different genre requires different approach in understanding and comprehending it. Developing the expertise in reading legal texts at an early stage of learning will be very beneficial to the students of law. This study examines the level of pre-university/foundation in law students’ awareness for the case law genre, and the aim of this study is to investigate the extent of awareness of the case law genre among the foundation in law students. Methods: Five students who were pursuing their study in the foundation/pre-university level were selected as the subjects in this study. Qualitative data were obtained through the think-aloud procedure and questionnaire which was administered after the think-aloud procedure. The transcription of each student’s verbal reports was scrutinised for evidence of genre awareness while the answers given in the questionnaire were used to support the findings of the study. Genre analysis of 4-Move structure was used to identify the students’ level of awareness. Results: The findings indicate that the students were aware of the case law genre. However, they displayed a mixed-level of awareness. Conclusion: It is hoped that this study can provide some insights into the reading behaviour of law students especially when reading case law. Knowing and understanding the case law structure is integral for law students, and analysing students understanding of reading case law can help both the students and English for Academic Purposes (EAP) educators.",
"keywords": [
"Genre analysis",
"reading skills",
"awareness",
"case law genre"
],
"content": "Introduction\n\nText genre awareness and recognising text types are an integral part of students reading process, as it can assist students in their academic and professional lives. As students, different text genre entails different approach to reading strategies. Law students are required to read extensively, and the reading materials include not only non-legal texts, but also specifically legal texts or legal genre. Law students being the novice readers of legal texts need to acquire and develop the specific reading skills at the early stage of their learning. Comprehending how genre is structured and organised will enable the students to intragenerically recognise and understand other texts within the same genre.1\n\nGenre studies and analysis are a situated linguistic behavior study within an institutionalised academic or professional setting, as well as a study on the identification of the typical generic structure and linguistic characteristics of the genre itself.2 The main focus on genre analysis is on its analysis of generic structures and rhetorical functions such as ‘moves’, ‘schematic’ or ‘generic’ structure. Bhatia (1991) highlights four noticeable competence areas for students to develop: knowledge understanding of the code, acquisition of genre knowledge, sensitivity to cognitive structures and exploitation of generic knowledge.3-5 In the legal genre, Bhatia (1993) proposes four different ‘moves’ structure that commonly appears in a case law:\n\nMove 1: Identification of the case\n\nMove 2: Establishment of the case facts\n\nMove 3: Arguments on the case facts\n\nSub-move I: Giving case history\n\nSub-move II: Presenting arguments\n\nSub-move III: Deriving ratio decidendi\n\nMove 4: Pronouncing on the judgement\n\nThe ‘moves’ familiarity and awareness will allow the law students to hone their reading strategies and comprehend the case law better. Case law is among the major sources of law in common law system, and central to law students’ curriculum. Christensen (2008) highlights that the earlier the students achieve the skills of reading judicial opinion (case law) effectively and efficiently, the better it is for the students to be more successful in their studies and their legal profession.6,7 However, reading case law is a huge challenge among the law students. Arrifin (2014) agrees that reading case law is a specific reading that requires law students to identify the material facts, the ratio and the issue of law, and to analyse the application of the legal principles in the judgments.8\n\nAs one of the universities in Malaysia that offers Bachelor of Law (Hons), Multimedia University (MMU) is the only private university with a Certificate in Legal Practice (CLP) exemption. MMU’s Law programme is either 1+4 years or 4 years of studies depending on the entry requirement. The 1-year programme called Foundation in Law programme is a pre-university equivalent, and it serves as an entry point to Bachelor of Law (4 years) for students with Malaysia Certificate of Education (SPM), an equivalent to General Certificate of Secondary Education (GCSE) in England. The 1-year foundation is a 3-trimester programme system.\n\nAcknowledging the significance of case law reading strategies among law students, and to better equip students with the expertise of reading as an expert, the study aims to:\n\n1. Examine the level of foundation in law students’ awareness of the case law genre.\n\n2. Investigate the extent of case law genre awareness of the foundation in law students.\n\n\nMethods\n\nA qualitative case study method through the think-aloud procedure9 was conducted in collecting the data. Participants selection was based on purposive sampling,10 and the criteria of achieving minimum grade A of their English SPM, studying law course and was in final trimester of foundation study, achieving an average 3.0 CGPA for the past 2 trimesters, and having the ability to verbalise at least 80% of their thoughts. Based on the criteria and agreement to participate in the studies, 20 students were selected for the think-aloud procedure practice sessions.\n\nFrom the practice sessions, five female students were narrowed down and selected as the participants of the study. Individually, the students recorded their think-aloud protocol procedure sessions within a 2-week time period. The students were categorised as Student 1, Student 2, Student 3, Student 4 and Student 5. Individually, each participant read the case law taken from The Malayan Law Journal11 (see Underlying data)12 and concurrently verbalised their thoughts loudly while reading the case law. The 10-structured post-questionnaire was administered immediately after the completion of the think aloud procedure (See Underlying data).12 All individual sessions were audio recorded and transcribed verbatim, and the post-questionnaire for triangulation purposes was given after they completed their think aloud protocol session. The think-aloud protocol transcription was coded, and then scrutinised for evidence of genre awareness based on Bhatia’s (1993) 4-Move genre analysis, and the post-questionnaire was used to supplement the think-aloud protocol.\n\nEthical approval (EA0682021) was obtained from Multimedia University. All 5 selected students were 18 years old, and their participations were voluntary, and anonymity was guaranteed. As the nature of the study is qualitative, all participants gave their oral consent in participating and contributing data for this study before each of the recording took place. They were given details on the nature of the study, and the needs to audio record their think-aloud protocol. All participants understood their required roles in the study, and that their data would be published in journals or conference proceedings. By agreeing to participate in the study, they conceded that they gave their consent.\n\n\nResults and discussion\n\nThe coded think-aloud protocol transcription analysis revealed that the foundation in law students showed a mixed-level of genre awareness of the case law. Table 1 shows the comparison of the students’ Moves with the Bhatia’s case law Moves.\n\nStudent 1 showed awareness of the case law genre, but she did not fully identify all the moves required in reading a case law. She fully identified Move 1, and 4. However, she did not recognise Move 2 as the full judgement section was like the headnotes section. She only managed to complete the first part of sub-move I and II of Move 3 by partially identifying the case history, reasons and the judgement made by the judge in addressing the second question raised in the case law. She did not identify the ratio decidendi (sub-move III of Move 3) and displayed any other indication of identifying the other arguments raised. She merely read and commented without making any connection to sub-move II and III. She clearly identified Move 4 by identifying the held sections. She clarified the judgement using her own understanding and concluded on the final judgement given by the judge. The data collected from the post-questionnaire supported her behaviour, and she admitted that knowing the structure would help her in understanding the case law better. Furthermore, her main strategy in reading case law was identifying the case issues. Interestingly, she was the only student who was aware that she was using different reading strategies when reading case law compared to reading non-legal genre. She claimed that the differences occurred because she was trying to explain further with more arguments rather than reading through the whole case. She only read what was important with regards to the case issue.\n\nStudent 2 was also able to identify several legal structures of the case law, but she did not complete the moves. Not only she did not identify Move 2, but she also did not identify sub-move II and III of Move 3. To student 2, there was no need to read everything in Move 3 as case understanding could be done by reading only the important information. Her justification may relate to the facts that in her lessons to read case law, she was taught to read both the headnotes section and full judgement. She noted that to understand what the case was about, she did not really need to read the full judgement. She was aware that the headnotes section provided her with pertinent information concerning the case, and the full judgement section of the case law provided the facts of the case and detailed information that she needed on how the judge had reached the decision. Even though she did not identify Move 2 and 3 she was still able to identify Move 4. She further admitted the importance of knowing the case law structure. To understand the case law, she only needed to summarise the full judgement. She admitted that there was no difference in her case law reading behaviour, and the reading strategies lessons that she learned in her English classes were sufficient to help her in understanding the case law.\n\nLike Student 1 and 2, Student 3 was also able to recognise Move 1, but she only identified the key features of the Move and did not identify all aspects. Then, she identified Move 2 and 3. Like Student 1, she only acknowledged the first part of sub-move II and III of Move 3. She recognised the second question and the arguments made by the judge, and the reasoning behind the judge decision, as well as the identification of the ratio decidendi. However, she did not recognise the arguments for the first question raised in the case. She completed her move by fully identifying Move 4. She agreed that understanding text structure would help in understanding the case flow, and it would be confusing if she did not know the structure. This would have hindered her case law understanding. She stated that she did not read differently, but she claimed that her English classes helped her in understanding the case law. She would also talk to herself while trying to find the case facts as her main reading strategy.\n\nStudent 4 was aware of several case law’s legal and structural signals like the headnotes section, the held section, and the full judgement of the case. She clearly identified Move 1, 2, 3 including Sub-move I and II and 4. Unlike the other students, she was the only student who could identify both issues raised in the case law. Interestingly, she did not manage to derive the ratio decidendi. She agreed that knowing the text structure would help her in identifying the facts and arguments put forward by counsels and the judgement. Her reading behaviour corroborated her data as she was able to identify Move 3 and 4. Furthermore, she stated that the strategy that she used to understand case law was to understand the facts and the main sources of the law applied in the case. However, she claimed that she did not utilise different reading strategies, and the reading strategies that she learned in the English classes were insufficient in understanding the case law.\n\nStudent 5 reading behaviour was marked with missing moves. She was the only participant who did not identify Move 1. She started her reading at the catchwords section and moved to Move 2. The same reading behaviour was also reflected in her Move 3 when she only recognised sub-move I. She said that the headnotes section of the case law was sufficient, and she chose not to read everything. Nevertheless, her reading behaviour showed confusion in identifying sub-move II and III of Move 3, and she was not able to fully identify Move 3. Although she managed to identify Move 4, her reading behaviour showed her difficulties in understanding the judgement. She acknowledged that she did not use any strategies, and she would usually read the case summary in the textbook before reading the case law. With regards to the question of the importance in knowing the structure of the text that she read, she stated that it could help her to acknowledge the details of the text, and to use the information for her arguments in subsequent cases. She also acknowledged that the reading strategies that she learned in her English classes only partially helped her as she was not taught on how to read case law in the English classes. Thus, she applied the same reading strategies when reading case law.\n\nThe data showed that majority of the students were not able to identify and complete Move 3. Move 3 was a very complex and important part of the case law as it revealed the arguments posed by the counsels from the opposing parties. These arguments would be supported by the interpretation of statues and case law which would be the main reference for the students if they encountered similar case. Similarly, Noraini (1997) concurred that her research participants displayed the identification, and they were also aware of the importance of Move 3, but she did not investigate further on the extent of students’ awareness on the structures.13 Holland & Webb (2006) assented the fact that reading case law required skills and interpretation which were built through experience.14 The findings in this paper also corroborated with Lunderberg (1987) who also consented that case structure knowledge empowered the readers to distinguish between language that signals the germane point of the rationale and language that signals dicta (judicial ramblings).15 Genre awareness and knowing the case law structure were important for law students.\n\n\nConclusion\n\nThe findings were intended to examine the level and extent of case law awareness among the foundation in law students. The findings revealed that the students demonstrated the knowledge of the rhetorical structure of a case law, but the level of awareness varied among the participants. Analysing students understanding of reading case law can help both the students and EAP educators. The sooner the foundation in law students achieve the skills to read legal genre like legal experts, the quicker they will succeed in the law school and in their future lives. A more comprehensive study can be done in relooking and revising the syllabus for the needs of exposing and teaching students how to read case law and other legal genre. Stratman (1990) highlights those legal educators have erroneously made the assumption that law students who enter law schools are fully equipped with sufficient literacy skills which are readily transferred to the legal texts.16 Thus, English for academic purposes practitioners and legal educators should contribute to the knowledge of reading a syllabus that can assist the students to read legal genre.\n\nThe study is only limited to the foundation/pre-university law students at Multimedia University, and as such the findings could not be generalised for all law students in other universities in Malaysia. It is hoped that this study can provide some insights into the reading behaviour of law students especially when reading case law.\n\n\nData availability\n\nDANS: Easy Genre Awareness among Foundation in Law Students\n\nhttps://doi.org/10.17026/dans-xnd-uts812\n\nThis project contains the following underlying data:\n\nData file: Data Submission Genre Awareness.odt\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\nAuthor contributions\n\nAbdullah, S. was involved with the conceptualisation, formal analysis, methodology, data collection, write up of the original draft and review & editing while Bhar S. K was involved with the write up, review and editing.",
"appendix": "Acknowledgment\n\nThe authors wish to thank the Multimedia Foundation in Law students’ participants for the supports of this study.\n\n\nReferences\n\nCandlin CN, Bhatia VK, Jensen CH: Developing legal writing. Engl. Specif. Purp. 2002; 21(4): 299–320. Publisher Full Text\n\nSwales JM: Genre Analysis. Cambridge: Cambridge University Press; 1990.\n\nBhatia VK: A genre-based approach to ESP material development. World Englishes. 1991; 10(2): 153–166. Publisher Full Text\n\nBhatia VK: Analysing genre: Language use in professional settings. London: Longman; 1993.\n\nBhatia VK: Worlds of written discourse: a genre-based view. London: Continuum; 2004.\n\nChristensen LM: The paradox of legal expertise: A study of experts and novices reading the law. BYU Educ. & L.J. 2008; 53(1): 53–87. Reference Source\n\nChristensen LM: Legal reading and success in law school: An empirical study. Seattle University Law Review. 2007. 30(1). (26 February 2006).Reference Source\n\nAriffin A: The reading of legal cases by Law undergraduates: Some problems and suggestions. Procedia. Soc. Behav. Sci. 2014; 134(2014): 109–118. Publisher Full Text\n\nEricsson KA, Simon HA: Verbal reports as data. Psychol. Rev. 1980; 87(3): 215–251. Publisher Full Text\n\nDecarlo M: Scientific inquiry in social work. 2018. Reference Source\n\nTANG SUNG MOOI V TOO MIEW KIM: The Malayan Law Journal. 3 MLJ 117, *; [1994] 3 MLJ 117.\n\nAbdullah, Senior Lecturer S (Multimedia University): Genre Awareness among Foundation in Law Students. DANS.2021. Publisher Full Text\n\nIbrahim N: Reading legal cases: An ethnographic enquiry. Thesis Master. Universiti Malaya. 1997.\n\nHolland J, Webb J: Learning legal rules. 6th ed.Oxford: Oxford University Press; 2006.\n\nLundeberg M: Metacognitive aspects of reading comprehension: Studying understanding in legal case analysis. Read. Res. Q. 1987; 22: 407–432. Publisher Full Text\n\nStratman JF: The emergence of legal composition as a field of inquiry: Evaluating the prospects. Rev. Educ. Res. 1990; 60: 153–235. Publisher Full Text"
}
|
[
{
"id": "119450",
"date": "01 Feb 2022",
"name": "Ina Suryani Ab Rahim",
"expertise": [
"Reviewer Expertise Genre analysis",
"English for Academic Purpose"
],
"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 reports on important issue of reading awareness among Law students, particularly on case law genre. The focus is on Foundation students, who are just beginning to develop a taste in reading legal texts which later will be very beneficial to the students of law. In addition to using a highly credible move model by Bhatia, the study also has obtained the appropriate ethical approval and consent.\nThe paper reports that the students demonstrated the knowledge of the rhetorical structure of case law, but the level of awareness varied among the participants. Perhaps this study is a part of a bigger study, which explains why the frequency pattern for the moves across the 5 readers remains ambiguous. Because data has not reached a saturation point due to small size of sampling, the conclusion for the finding has to be tactfully written. Having a size of five readers to test the protocol procedures and the potential of using Bhatia’s move model is a justified choice. However, the size of five is not to be used as conclusion to generalize the knowledge of the foundation group of students, even for foundation/pre-university law students at Multimedia University as claimed in last paragraph of the paper “The study is only limited to the foundation/pre-university law students at Multimedia University…”. Because of the small size, rather than claiming that the finding describes the way of reading for the foundation law students in MMU as in the last paragraph of the paper, it is safer to reassert the claim made in the initial part of the paper that limits the finding to the participants in the study. The data is not conclusive as it did not reach saturation for the group so it is questionable that the conclusion of the findings provides insights into the reading behaviour of foundation law students in MMU especially when reading case law. It is suggested that this claim is reworded and hedging is used.\nBrief explanation on each move in Bhatia’s model would also enhance the paper in terms of clarity. Given the potential for future study using bigger sampling, it is suggested that future analysis is presented in a thematic style, according to the fulfilment of the moves rather than explaining each of the students’ experiences as done in this study. The paper also need to have more recent works related to the topic.\nOverall, the paper is useful and supports better understanding for English for academic purposes practitioners and legal educators.\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? 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? Partly",
"responses": []
},
{
"id": "179536",
"date": "05 Jul 2023",
"name": "Adlina Ariffin",
"expertise": [
"Reviewer Expertise Applied linguistics",
"legal English",
"English for Specific Purposes",
"sociolinguistics",
"second language acquisition."
],
"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 strives to examine the level and extent of awareness of the case law genre among selected law foundation students. It is a good study, however, as far as the report is concerned, below are my comments:\nSince this is a brief report, the article did not provide clear explanation especially on the methodology of the study which would allow for future replication. For example, it was mentioned that 5 students (from the initial 20) were selected after the practice session. The paper needs to explicate what the 'practice session' entailed and how the 5 students were selected.\n\nSome information should be given on the chosen case law & the selection criteria.\n\nSome relevant items from the questionnaire should be shared to give a better idea to the readers.\n\nSome information on how the think-aloud procedure was implemented in the study should be given.\n\nIn the results section, it was mentioned that 'the law students showed a mixed-level of genre awareness'. This was followed by the description of how each student fared based on the data from the think-aloud procedure and the questionnaire. Nevertheless, readers are not able to understand how the analysis of these methods led to the conclusions made in the study. For example, it was mentioned that Student 1 could fully identify Move 1 & 4. However, the paper did not describe how such deduction was made. The same concern applies to the results presented in Table 1. Furthermore, in terms of the identification of the Moves, there needs to be a clear demarcation or definition of the different categories - full identification, partial and no identification.\n\nIn terms of the presentation of the results, it is opined that it would be more affective and interesting if they were explicated based on the Moves rather than the students.\n\nThe literature needs to be updated.\n\nFinally, the paper requires proof reading before indexing.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-28
|
https://f1000research.com/articles/10-385/v1
|
13 May 21
|
{
"type": "Research Article",
"title": "Development of a computer-assisted instructional package for life skills to prevent risky sexual behaviors in early adolescents, Bangkok, Thailand",
"authors": [
"Wanida Neranon",
"Ladaporn Thongsong",
"Wanida Neranon"
],
"abstract": "Background: The purpose of the present study was to examine the effects of a newly developed computer-assisted instructional package for life skills (CAIFLS) specifically designed to raise awareness of risky sexual behaviors among Thai early adolescents in Bangkok. Methods: The research process included two phases: (1) the development and (2) the use and evaluation of the newly developed CAIFLS package. First, 5 teachers and 5 Grade 7 students of a Bangkok school were interviewed to collect information needed for the development of CAIFLS. The second phase was to implement learning activities through CAIFLS with a total of 87 Bangkok school students, consisting of 44 students for the experimental group who received CAIFLS for 4 sessions, and 43 students for the control group who received routine class lecture. CAIFLS instructions, lesson plans and worksheets were designed as the experiment methods. Then questionnaires of life skills assessments and student satisfaction were used to investigate the effects and the student satisfaction of CAIFLS. Results: The findings revealed that the efficiency values of the CAIFLS package were 80.2/82.5, higher than the set criteria of 80/80. Mean scores on life skills for the experimental group significant increased (p < .05), which was higher than the control group. The students also showed their satisfaction of CAIFLS at a high level (M = 4.20, S.D. = 0.29) Conclusions: CAIFLS can be used as an effective learning tool to enhance life skills to prevent risky sexual behaviors among Thai early adolescents.",
"keywords": [
"Prevent Risky Sexual Behavior",
"Early Adolescents",
"Activity Package",
"Computer Assisted Instruction",
"Life Skills",
"Development"
],
"content": "Introduction\n\nHigh-risk sexual behaviors, especially in early adolescents, are one of the primary concerns in many countries. In Thailand, it was reported that the average age of early adolescents’ first sexual intercourse was 12 years (Bureau of Reproductive Health, 2017). Statistics in 2014 showed that female adolescents aged 15-19 gave birth at the rate of 47.9 cases compared to 1,000 among the entire population at the same age (Bureau of Reproductive Health, 2017). The tendency of child pregnancy seems higher, which leads to physical, mental, economic and social problems, e.g. abortion, sexual transmitted diseases, divorce and lack of experience in taking care of children (Unite of children, 2015). In the 2015 academic year, of 8,814 cases of student dropout, 4,019 cases were lower secondary school students (Chuaykaew et al., 2018; Ministry of Education, 2016). In addition, it was found that the childbirth rate of Bangkok teenagers aged 15 to 19 years old was at 43.30 per 1,000 female adolescents in 2013-2015 (Bureau of Reproductive Health, 2017). This, together with the problems mentioned earlier, was likely attributed to Thai early adolescents’ lack of sexual health knowledge (e.g., sexual relationship, high-risk sexual behavior, birth control) despite the fact that sex education is mandated and promoted in schools (Mahanta et al., 2016).\n\nPreventing early adolescents from having premature sex should be started when they enter reproductive age, which is between the ages of 12 and 13 (Grade 7) to prevent sexual behavior problems in the future. Based on the analysis of a thesis of public health nursing in children and early adolescent in schools, life skills can influence behavioral changes (Widman L, et al., 2016). Life skills development is crucial for early adolescents, for example, to think critically, solve problems appropriately and communicate effectively, especially in prevention of sexual behaviors (Paknoi, 2017; Prabmeechai & Rueangworaboon, 2017). However, from previous studies it has been seen that Thai early adolescents have insufficient life skills in problem solving; resulting in inability for self-adjustment and making developmental changes (Bunnag et al., 2013; Butcharoen et al., 2012). The practical use of life skills is significant for their daily life, and adolescents should maintain appropriate skills to protect themselves from risky sexual behaviors. The World Health Organization has defined ‘Life Skills’ as “abilities for adaptive and positive behaviors that enable individuals to deal effectively with the demands and challenges of everyday life” (World Health Organization, 1994).\n\nPrevious research has studied the development of student training courses to prevent sexually risky behaviors in a secondary school in Bangkok and found that students needed to learn about gender-related life skills in four areas, namely relationship building skills, communication-denial skills, self-esteemed skills, and self-awareness skills. Relationship building skills are the abilities to build good relationships with each other, to understand the differences between three stages of relationship (Stage 1 - Friendship, Stage 2 - Love, and Stage 3 - Sexual relationship) and to maintain friendship or non-sexual relationships. Communication-denial skills are the ability to communicate or express one’s feelings of thought appropriately with culture and circumstance through, for example, opinions, negotiations, or denials. Self-esteem is the ability to control and value one’s self by not having risky sexual behaviors, including dating, hanging out or being alone with friends of the opposite gender in private places, reading or watching media that have sexual content, kissing, touching, or drinking alcoholic beverages before having sex. The fourth area of self-awareness is the ability to observe, know and understand one’s self (e.g. strengths and weaknesses, needs) as well as to be aware of inappropriate school-age sexual behaviors that can have an impact on their body, mind and society. These four life skill aspects in relation to sexual behaviors are also found in literature in that if students lack relationship building skills, they will not be able to distinguish an emerging relationship, whether it is friendship or love, which could destroy good relationships between friends (Sirited P, 2018: Thiammok & Saranrittichai, 2017: Wongjunthong & Rachawijit, 2010). Also, if they do not possess communication-denial skills, they might use inappropriate denial strategies (e.g., involving aggression) when disagreeing on opinions or denying requests in relation to high-risk sexual behaviors from others (Kirdin S et al., 2019: Olanratmanee B, 2018). Students who lack self-esteem skills will not be able to control or value themselves. There is a trend among early adolescents that having a partner in school age or having multiple partners is currently acceptable. Inappropriate sexual behaviors between men and women, e.g. touching body parts, going clubbing, wearing seductive dresses, drinking alcohol or using illegal drugs, has led to an increasing sexual intercourse rate (Butcharoen et al., 2012: Kylene G. et al., 2012). In addition, if the students lack self-awareness, they will not be able to understand themselves or to identify their strengths and weaknesses (Kosalavit T et al., 2017). Therefore, enhancing life skills among early adolescents is very important in order to help them protect themselves from risky sexual behaviors they might be facing in society. Teaching life skills needs the participation of early adolescents to reflect their thoughts and feelings from their previous experiences, build interactions, and create new knowledge together.\n\nA review of life skills in preventing sexual risky behaviors of early adolescents and interviews with students found that preventing sexual risky behaviors focuses on sex education, positive attitudes towards sex, and life skills teaching through lectures, group discussions, role-playing, with the use of various types of media (e.g. brochures, videos, short films, demonstrations) (Tungsaengsakul S et al., 2017: Kosalavit Tet al., 2017). To the best of our knowledge, computer-assisted instructions (CAI) has not been adopted to promote life skills in preventing sexually risky behaviors, but has been used to promote sex education in early adolescents in Thailand (Wongjunthomg K & Rachawijit J, 2010: Eamratsameekool W, 2008). However, currently early adolescents, who have been raised and surrounded by new technologies and various media, have unique learning styles, need freedom and want to learn new things through innovative and interactive platforms. . It is evident in the literature that young adolescents can learn things quickly and easily from innovative media around them (Bertrand, 2006: Sangchart E & Duangsong R.,2016). Thus, media used for their learning should be suitably designed to help stimulate their interest in learning. CAI is one learning tool with features for presenting multi-media content on a computer that can promote student learning and also life skills to prevent sexually risky behaviors among early adolescents (Alessi S.M. & Trollip S.R., 1985; Bualoy et al., 2014; Sasinun et al., 2013). It can help students to learn difficult content more easily in a short time, which responds to students' needs and self-learning (Kanokthavomtham A & Lalognum N, 2017; Krungkraipetch, 2019). CAI is also a virtual-reality teaching medium that plays a role in education by using computers to help create learner-centered lessons (Ratta S. et al., 2015). It promotes self-learning through new experiences from characters, animations, colors, and sounds that help attract students to interact with the lessons and increase learning motivation and understanding (Wongjunthomg K & Rachawijit J, 2010: Chaisatsampun W & Jittrapirom A, 2017).\n\nThus, the present study is aimed at developing and studying the results of a series of computer-assisted lessons to promote life skills in preventing sexual risky behaviors in early adolescence. It is hoped that the newly developed CAI lessons can reduce school-age sexual intercourse, teenage pregnancy, or sexually transmitted diseases.\n\n\nMethods\n\nThis Research and Development Project was approved by the Institutional Review Board, Kuakarun Faculty of Nursing, Navamindradhiraj University (approval number KFN-IRB2018-19 and KFN 22/2019). Information about the study was explained to the students; objectives, data collection steps, timing of research study, and benefits of participation in the research project were given to the students, their guardians and teachers prior to conducting the study. Written informed consent to participate in the study was signed and obtained from the students and their legal guardians. They were paid for participation in this research project, as approved by the Research Fund Board of the University. Upon completing the interview, each participant received 300-baht cash incentive for their participation.\n\nThe research project was divided into two phases; phase 1 developed the computer-assisted instructional package for life skills (herein ‘the CAIFLS’). In phase 1, the CAIFLS was validated using pilot testing. In phase 2, the efficacy of CAIFLS was tested in a group of secondary school students using a questionnaire. In phase 2, student satisfaction with CAIFLS was also evaluated.\n\nDevelopment of CAIFLS package\n\nTo understand life skills (LS) in preventing sexual risky behaviors in Thai early adolescences, the CAIFLS and a questionnaire were systematically developed by the researchers. First, background information was synthesized by reviewing textbooks, research studies, articles. After the researchers reviewed and synthesized the theory of LS and related research, a group of participants in a school in Bangkok were sampled to participate in interviews for a situation analysis of current risky sexual behaviors in the school.\n\nThe participants in the interviews were purposively sampled from two target groups of participants, i.e. students and teachers. Five students were selected based on the criterion of differences in their academic achievements (GPA) (1 high-, 2 moderate-, and 2 low-GPA students) and gender (3 females and 2 males). The second group consisted of 5 teachers who were responsible for guidance, advisory teacher, Health-Physical Health Education and administration. Two sessions of group interviews with teachers and students were conducted to gather information about current high-risk sexual behaviors in school students (Extended data (Neranon & Thongsong, 2021b)). Then the researchers analyzed the collected data from the group interviews and the contents, including life skills needed to prevent or reduce the sexual risk behaviors in early adolescents, guidelines for promoting life skills in preventing early adolescent sexual risk behaviors, and the characteristics of preferred teaching materials. After the data analysis, the researchers developed a series of computer-assisted lesson activities to promote life skills in preventing sexually risky behaviors for early adolescents in four main aspects: 1) relationship building skills; 2) communication–denial skills; 3) self-esteem skills; and 4) self-awareness skills.\n\nCAI lesson series entitled ‘Adolescents and life skills on sexual self-prevention’\n\nThe CAI was divided into three steps (Alessi S. M & Trollip S.R., 1985): 1) planning step: comprised of define the scope, cost the project, produce a planning document; 2) design step: comprised of develop initial content ideas, conduct task and concept analyses, preliminary program description, prepare a prototype, create flowcharts, storyboards and prepare scripts; 3) development step: write program code, create the graphics, produce audio and video, test and make revisions.\n\nThe final version was developed in the form of Adobe Flash Player. It features two-choice pre- and post-tests to measure life skills to prevent sexual risky behaviors in early adolescents. Once the students complete the tests, they can see the scores they have achieved. For the post-tests, the students can see the correct answers of all items. Students’ pre- and post-test scores are recorded in the program. The program was created and designed using still images and animations with vivid colors, voiceover, and subtitles. Four lessons were developed based on situations that students encounter in everyday life. The series of CAI included: 1) relationship building skills; 2) communication–denial skills; 3) self-esteem skills; and 4) self-awareness skills.\n\nThe four lessons\n\nThe lesson plans included activity topics, learning objectives, tools/materials used, worksheets, the duration of each activity, and leaning assessments. The worksheets for each activity are as follows and copies in Thai are provided in the Extended data (Neranon & Thongsong, 2021b):\n\n1. Relationship building skills: Two worksheets were used for two activities. The first worksheet for an activity entitled ‘What stage is it?’ comprised short descriptions of relationship situations and the student needed to identify the stage that the relationship was in (i.e., Stage 1 - Friendship, Stage 2 - Love, or Stage 3 - Sexual relationship). The other worksheet was designed for an activity entitled ‘Is it appropriate?’. This activity requires the students to role play based on situations of both appropriate and inappropriate relationship building.\n\n2. Communication–denial skills: A worksheet for an activity entitled ‘What would you say?’ was given, allowing the students to complete incomplete conversation using refusal skills for various situations.\n\n3. Self-esteem skills: A worksheet for an activity entitled ‘I’m proud of myself’ was provided. The students needed to provide answers and reasons why they would or would not perform such behaviors given in each situation.\n\n4. Self-awareness skills: Two worksheets were used for two activities. The first activity entitled ‘This is right!’ asked the student to identify behaviors that should or should not performed with friends of the opposite gender. The second activity entitled ‘What’s happening?’ required the students to analyze causes and provide solutions for each problem.\n\nValidation of CAIFLS\n\nFive experts in the field of preventing risky sexual behaviors in children and adolescents and educational technology were approached to validate the CAIFLS. All experts used a 39-item evaluation checklist of 5-point Likert scale developed by the researchers to assess the quality of CAIFLS in terms of content (10 items), functionality (19 items), as well as lesson plans and worksheets (10 items). It was found that the CAI content was of quality at a very good level (M = 4.44, SD = 0.206), the CAI functionality was at a very good level (M = 4.86, SD = 0.328), and the quality of the activity plans and worksheets of activities for preventing risky sexual behaviors for early adolescents was also at a very good level (M = 4.42, SD = 0.175). The researchers then improved the quality of the CAIFLS based on the suggestions given by the experts.\n\nA pilot test of CAIFLS was performed with students in Bangkok having the same characteristics as the target participants, which were students aged 12–13 years studying in Grades 7 students in schools of Bangkok. The efficiency of the CAIFLS was examined by the students using the E1/E2 formula as follow. The findings of efficiency analysis of the CAIFLS activity package based on 80/80 criteria (or the E1/E2 formula) showed the efficiency values; the first try out with individuals (three students) gave results of 65.0/61.5, which were lower than the set criteria. Misspelled words in CAIFLS were corrected and the questionnaires were reordered. The second try out with a small group (10 students) gave results of 75.0/78.0, which were also lower than the criteria. The language used in the questions were revised for appropriateness for the students. The final try out with a larger group (30 students) gave results of 81.0/82.5, which were higher than the criteria (Figure 1).\n\nParticipants\n\nSample size was determined by the effect size of 0.55. The power analysis was set at 0.8 at the 0.05 level of significance (Cohen, 1988) and tested with one-tailed test by using G*power to obtain 42 sample size for each group. In order to avoid losing cases, 5% of the sample (n = 3), were included into each group (Faul et al., 2007). Therefore, the sample size was 45 participants for each group. They were assigned into the experimental and control group.\n\nPurposive sampling of one secondary school in Bangkok was conducted. This school has been reported by teachers as having a problem with risky sex behavior. Simple random sampling was then used to select two classrooms. One classroom was the experimental group, with 44 students, and one classroom was the control group, with 43 students. The participants of the present study had a total 87 students.\n\nInclusion criteria: secondary school students aged 12–13 years studying in Grades 7 in schools of Bangkok, with the ability to read, write, and communicate.\n\nDevelopment of the assessment questionnaires\n\nTwo questionnaires were developed to analyze if the objectives of CAIFLS were successful (questionnaire 1) and to see student satisfaction with the CAIFLS (questionnaire 2) (Extended data (Neranon & Thongsong, 2021b)).\n\nQuestionnaire 1: A two section questionnaire. Section one contained a checklist to obtain general demographic information; section two consisted of 33 items included the following sections:\n\n1.1 Relationship building skills on prevention for risky sexual behaviors. There were 10 items with rating scales from 1-5 (5 = Totally agree, 4 = Agree, 3 = Partly agree, 2 = Disagree, 1 = Totally disagree). The items included both positive and negative statements.\n\n1.2 Communication–denial skills for risky sexual behavior prevention. There were 5 items of multiple choice format (1= right and 0 = wrong).\n\n1.3 Self-esteem skills on prevention for risky sexual behaviors. There were 8 items with rating scales from 1-5 (5 = very high, 4 = high, 3 = fair, 2 = low, 1 = very low). The items included both positive and negative statements.\n\n1.4 Self-awareness skills of risky sexual behaviors. There were 10 items with rating scales 1-5. (5 = Totally agree, 4 = Agree, 3 = Partly agree, 2 = Disagree, 1 = Totally disagree). The items included both positive and negative statements.\n\nQuestionnaire 2: Consisted of 10 items with rating scale 1-5 (5 = mostly satisfied, 4 = more satisfied, 3 = moderately satisfied, 2 = less satisfied, 1 = not satisfied).\n\nValidation of questionnaires\n\nContent validity of the questionnaires were evaluated by five experts in the field of preventing risky sexual behaviors in children and adolescents. All of the experts worked as child health specialists in Bangkok, including two child health and behavior specialists, two school health nurse, and one educational technology. The five experts assessed the items of the two questionnaires using the Index of Item Objective Congruence (IOC). The assessment of the questionnaire items showed that most of the items were at a high level of item-objective congruence (IOC ≥ 0.5), except only one item (IOC = 0.4) of questionnaire 1. Subsequently, the researchers revised the questionnaire items based on the experts’ feedback in terms of content, language use, and appropriate context representation for children aged 12–13 years in Bangkok.\n\nA pilot test was performed with 30 secondary school students in Bangkok having the same characteristics as the target participants, which were students aged 12–13 years studying in Grades 7 students in schools of Bangkok, with the ability to read, write, and communicate with normal, Reliability was analyzed using Cronbach’s alpha. It was found that the reliability values of the two questionnaires were greater than 0.80, which is at a good level. The revised version of the instruments were then used for data compilation (Figure 1).\n\nData collection\n\nAfter obtaining consent from the students and their legal parents, a group of trained research assistants coordinated with the teacher coordinators of the schools. Then the researchers and research assistants went to the participants’ schools to collect data. Before starting compiling data, the researchers and research assistants gave self-introduction, expressed the purpose of the research clearly, and clarified the data collection details to each of the participants.\n\nAfter having understood all the research-related information, each participant was given questionnaire 1 to complete (Pre-test) (generally 30 to complete).\n\nThe group of 44 participants assigned to the experimental group received the CAIFLS program. The participants of this group received a total of 4 lessons, 60 minutes each. The group of 43 participants assigned to the control group received no CAIFLS.\n\nAll participants in both groups completed questionnaire 1 after the CAIFLS intervention had been completed (post-test) (Figure 2). Students then completed questionnaire 2.\n\nStatistical analysis\n\nDescriptive statistics were utilized for data analysis of demographic information (section 1, questionnaire 1), and the level of student satisfaction on CAIFLS (questionnaire 2).\n\nFor questionnaire 1 (section 2), frequency distribution testing was done using the Kolmogorove-Smirnov Test formula, and normal curve distribution was confirmed. Therefore, a t-test at.05 level of statistically different significance was used to evaluate the effect of the CAIFLS. All statistical analyses of the present study were conducted using SPSS software version 26 (IBM Corp., 2019).\n\n\nResults\n\nThe participants were 87 students who were early adolescents studying in Grade 7, in Bangkok. A total of 44 students (males 47.75%, females 52.3%) were assigned as the experimental group, and 43 students (Males 48.8%, females 51.2%) were in the control group. Their average age was 12 years. The average academic achievement (GPA) was between 2.50 and 2.99.\n\nThe efficiency (E1/E2) analysis of the CAIFLS based on 80/80 criteria with the experimental group (44 students) was 80.2/82.5, which was higher than the criteria.\n\nTo test for differences before and after the intervention, mean scores of the four variables (i.e., relationship building skills, communication-denial skills, self-esteem skills and self-awareness skills) were evaluated.\n\nWithin the control group (n = 43) no significant differences were found in the mean values of the four variables between pre-test and post-test scores. Within the experimental group (n = 44), significant differences were found in all variables (Table 1). Significant differences were also found between the control group and the experimental group (n = 44) after the intervention (post-test) for the mean scores on the four variables (Table 2).\n\n** p < .01.\n\nTable 3 presents the satisfaction of the experimental group with the CAIFLS package after finishing the intervention. The CAIFLS satisfaction of the experimental group was found at the level of ‘more satisfied’.\n\n\nDiscussion\n\nThe CAIFLS lesson series developed by the researchers improved teaching efficiency in building life skills to prevent risky sexual behaviors of early adolescents. This was shown by the efficiency values from CAIFLS validation, which were above the set criteria (80.0/80.0). The experimental group had higher average post-test scores for life skills in preventing risky sexual behaviors after the intervention than the pre-test scores. The post-test scores of the experimental group were also higher than the post-test scores of the control group. This indicates that the learning process of the experiment group developed because the lesson series of CAIFLS strengthened their life skills in preventing sexually risky behaviors of early adolescents. As a newly developed and carefully designed instructional media, the CAIFLS has various tools (the CAI lesson series entitled 'Adolescents and Life Skills on Sexual Self Prevention’, group discussions, role-playing activities) to help students develop their life skills in preventing high-risk sexual behaviors.\n\nThe characteristics of CAI meet the differences between individuals, helping learners to study according to their abilities through well-arranged learning content which allows learners to learn step by step (Kanokthavomtham & Lalognum, 2017: Krungkraipetch, 2019: Vatanasomboon P et al., 2018). Based on the results of the questionnaire on opinions and satisfaction of the experimental group towards the CAIFLS lesson series, it was found that the lesson series can engage the learners for learning. They further mentioned that they liked the colorful cartoon images along with clear voice-over. The content was divided into small lessons, making the students keep learning with interest. This is in line with Krungkraipetch (2019), who suggests that a good cartoon platform and good audio-visual score incentivizes students to learn more. The questionnaire results further showed that the lesson series had necessary basic information, e.g. learning objectives, functions. The CAIFLS lesson series had clear instructions, learning objectives, main menu, submenu, and exit buttons, which is user-friendly for self-learning without time restrictions for learning. This is supported by previous research (Sukpom T et al., 2017: Wongjunthong K & Rachawijit J.,2010) that studied the effects of learning achievement on sex education in Grade 8 students through a computer-assisted instruction program, which revealed that the students enjoyed learning through the CAI learning program because its instructions and learning content were easy to understand. Another prominent feature of the CAIFLS is that the difficulty level of the content and the language used in the series was suitable for the target learners. The participants of the experimental group agreed that the lessons were easy to follow and understand, and topics of the lessons were related to their everyday life. In addition, based on our observation, the majority of students paid attention to the lessons while learning. They did not talk to their peers but enjoyed the lessons as they laughed or smiled. However, the participants of the study were quite worried about taking the tests after lessons. Some took longer time to complete the tests as they were afraid of giving wrong answers.\n\nWith regard to relationship building skills, it was found that the experimental group had higher post-test scores than their pre-test, and they also had significantly higher post-test scores than the control group. This can be because simulations were assigned through the CAI topic entitled Relationships building. The content was a scenario to learn how to build good relationships with each other in order to understand the differences between three stages of relationships (i.e., Stage 1 - Friendship, Stage 2 - Love, and Stage 3 - Sexual relationship) and to maintain friendships or non-sexual relationships. After completing the lesson, the participants of the experimental group were divided into small groups to discuss the situation given in the activity entitled “Which state is it?” and compose dialogs based on their discussion. Subsequently, each group performed their role-play for the activity entitled “Is it appropriate?” using their own dialogs in front of the class. This activity indicated that the practice in this aspect was relevant to real-life situations (Chiengta et al., 2018). The students were able to exchange their competencies to solve problems and to select appropriate approaches in building better relationships with other people without breaking them (Mahanta et al., 2016; Kosalavit et al., 2017; Sirited, 2019). The researchers observed the students as they were role-playing and found that the students seemed to have a good tendency to express friendships with their peers. However, there were some groups of students who expressed their adolescent emotions, fieriness, and also needs for peer acceptance, expressing themselves for a loving relationship.\n\nFor communication–denial skills, the experimental group had higher post-test scores than their pre-test, and they also had significantly higher post-test scores than the control group. The simulations were assigned under the CAI topic Effective Communication. The content allowed the students to appropriately communicate their thoughts to the situations given, using negotiation or denial skills. After the CAI lesson, small group discussions were gathered to discuss problems and to compose dialogues given in the worksheets (Think Hard), and to practice a communication skill of Saying No (or Denial) which exists in everyday life. The students in each group performed role plays based on their own dialogues in front of the class. Consequently, they had opportunities to exchange opinions focusing on the actual practices (Kosalavit et al., 2017; Heednakham et al., 2015), which made them build their own knowledge (Sasinun et al, 2013). This is in line with Bualoy et al. (2014) who investigated the effectiveness of a sex education program to prevent sexual risk behavior on Grade 8 students in Sampran District, Nakhonpathom Province. They used real sexual behavior problems with the students and found that the students had risky sexual behaviors at a lower rate. The present study showed the same results in that most students had a good tendency to express their negotiations or denials, but there were still some students that used words to communicate in an aggressive way, for instance some female students pushed male student's hands and aggressively blamed them immediately, showing inappropriate communication skills in real situations.\n\nAs regards to self-esteem skills, the findings showed that the experimental group had significantly higher post-test scores than their pre-test, and they also had significantly higher post-test scores than the control group. Simulations were assigned under the CAI topic Self-esteem. The lesson was to make the students aware of self-value, for example, not to dress provocatively or hang out with a friend of opposite gender alone or in a private place. The students of the experimental groups developed the self-esteem skill in small groups following the instructions given in the worksheet. The students were required to think critically, share their opinions, and expressed their thoughts on the flipcharts to confirm their thoughts and self-values relating to non-conformities to risky sexual behaviors (Olanratmanee, 2018: Thamrongsotthisakul W., 2017). The researchers examined the students' responses given in the worksheet of the lesson and found that most students had good prospects. They were able to provide reasons for self-esteem that they would not behave inappropriately. For example, a female student said that she would not dress provocatively due to an increase in number of rape and sexual assault cases on girls.\n\nFor self-awareness skills, the experimental group had significantly higher post-test scores than their pre-test, and they also had significantly higher post-test scores than the control group. The simulations were assigned through the CAI topic entitled Self-awareness. The lesson made the students aware of their strengths and weaknesses as well as their needs and unwanted needs. The lesson also let the students aware that watching sex videos, hugging, kissing, touching body parts, or drinking alcoholic beverages were examples of inappropriate sexual behaviors which can lead to sexual problems, e.g. sexual intercourse or school-age pregnancy. After the CAI lesson, the students discussed problems provided in the worksheet in small groups. During the activity, the students brainstormed many ideas about risky sexual behaviors in various situations. Through this activity, the students analyzed their own weaknesses and strengths. They comprehended more clearly about their own needs and individual differences of other people (Bualoy et al., 2014: Phumjuntuk & Duangsong R, 2011: Widman L et al, 2016). The students in each discussion group shared their constructive ideas to find appropriate approaches to protect themselves from risky sexual behaviors. The researchers examined the student's responses in the worksheet of the lesson and discovered that students had a good tendency to identify appropriate and inappropriate behaviors. They were also able to tell what to do in order not to put themselves in a situation where there is a risk of sex.\n\nBased on the findings of the present study, one conclusion can be made that the CAIFLS package can be used as an effective tool to prevent risky sexual behaviors in early adolescents. However, it can also be concluded that CAIFLS package should not be used as a single learning source since it might limit learning or correct understanding of the students towards the topics. It needs to be used by a knowledgeable teacher since it requires human interactions, discussions, question and answer sessions, and role-playing activities involved in order to effectively promote life skills for risky sexual behavior prevention in Thai early adolescents for their better understanding.\n\nThis study evaluated the effectiveness of the CAIFLS learning package with Grade 7 students in only one school in a Bangkok district. This CAIFLS learning package should be further used in other districts and in more schools.\n\nAlthough the CAIFLS learning package can be adopted to promote life skills for risky sexual behavior prevention, teachers that intend to use this learning package are encouraged to be trained how to use this learning package effectively before use in their classrooms.\n\n\nConclusions\n\nIt can be confirmed that the CAIFLS can be effectively applied as an educational media for teachers, pediatric nurses, school health nurses, and related school personnel to be used for promoting life skills of the early adolescents to prevent risky sexual behaviors in schools or communities.\n\n\nData availability\n\nUnderlying data cannot be shared as the ethical committee that approved this study states that only aggregated data can be shared openly. In addition, the consent form that guardians/children signed explicitly stated that the data resulting from the study would not be openly shared. Researchers 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: Development of activity package computer assisted instruction for life skills to prevent risky sexual behaviors on early adolescents, Bangkok, Thailand, https://doi.org/10.17605/OSF.IO/KHPXD (Neranon & Thongsong, 2021b).\n\nThis project contains the following extended data:\n\n- Interview questions for Thai students and teachers (in Thai)\n\n- Questionnaires CAIFLS for Early Adolescents, research instrument in English\n\n- Worksheets for CAIFLS (in Thai)\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\nSoftware availability\n\nCAIFLS program available from: https://docs.google.com/forms/d/16NLKoSJjW49QSULlSkOUFPXnVDvmUuddaHXnCy9WHac/edit\n\nSource code available from: https://github.com/Neranon/WN-CAIFLS\n\nArchived source code as at time of publication: http://doi.org/10.5281/zenodo.4539903 (Neranon & Thongsong, 2021a).\n\nLicense: MIT",
"appendix": "Acknowledgements\n\nThe authors would like to thank the Research Fund of Navamindradhiraj University for a research grant allocated. The authors would like to appreciate and thank all adolescents and teachers who kindly spent their time to participate in this research.\n\n\nReferences\n\nAlessi SM, Trollip SR: Computer-based Instruction: Method and Development. New jersey: Prentice-Hall; 1985.\n\nBualoy W, Therawiwat M, Vathanasomborn P, et al.: Effective of a sex education program to prevent sexual risk behavior on grade 8 student, Sampran District, Nakhonpathom Province. Rama Nurse J. 2014; 20(1): 127–142.\n\nBunnag R, Temsirikulchai L, Vatanasomboon P, et al.: Effectiveness of life skills program for preventive sexual risk behaviors of secondary school Students, Nakhonpathom Province. Thai J Public Pealth. 2013; 43(1): 80–93.\n\nBureau of Reproductive Health, Department of Health: Statistics on Adolescent Births, Thailand. 2017.Reference Source\n\nButcharoen W, Pichayapinyo P, Pawwattana A: Factors related to sexual risk behavior among Thai secondary school students. Journal of Public Health. 2012; 42(1): 30–40.\n\nChiengta P, Tumchea S, Maneechot M, et al.: Effects of a sexual health promotion program on pregnancy prevention of teenage in Saraburi Municipal. J Boromarajonani College of Nursing, Bangkok. 2018; 34(2): 101–111.\n\nChuaykaew B, Chenglai N, Pichairat A, et al.: Factors related with sexual risk behavior in early adolescents in Trang Province. The Southern College Network Journal of Nursing and Public Health. 2018; 5(1): 240–256.\n\nCohen J: Statistical power analysis for the behavioral sciences. (2nd ed). Hillsdaler, New Jersey: Lawrence Erlbaum Associates Publishers; 1988.\n\nFaul F, Erdfelder E, Lang AG, et al.: G*Power 3: A flexible statistical power analysis program for the social, behavioral and biomedical sciences. Behav Res Methods. 2007; 39(1): 175–191. PubMed Abstract | Publisher Full Text\n\nHeednakham U, Kasatpibal N, Viseskul N: Effect of parent communication skill development on communication about HIV prevention between parent and early adolescents. Nursing J. 2015; 42suppl 1: 13–24.\n\nIBM Corp:IBM SPSS Statistic for Windows, Version 26.0. Armonk, NY: IBM Crop; 2019.\n\nKanokthavomtham A, Lalognum N: The development of computer-assisted instruction by using the Gagne's nine events of instruction on sex education for Mathayom 2 students. J Education Naresuan Univ. 2017; 21(4): 329–341.\n\nKirdin S, Vuthiarpa S, Bunthumporn N: Effects of life skills program on knowledge and life skills to prevent sexual assault in female secondary school students. J Psychiatric Nursing Mental Health. 2019; 33(1): 128–145.\n\nKosalavit T, Kanyakan K, Sutthilukmunikul S, et al.: The effectiveness of health education program by applying life skills and social support in preventing HIVs behaviors in Mattayom 2 students in Ubon Ratchathani Province. J Ratchathani Innoovation Health Sciences. 2017; 1(1): 45–63.\n\nKrungkraipetch K: Sex Ed. CAI Creation for Young Teen in Thailand. Thammasat Medical J. 2019; 19(3): 502–518.\n\nKylene G, Deb L, et al.: Interventions using new digital media to improve adolescent sexual health. J Adoles Health. 2012; 51(1): 535–543. Publisher Full Text\n\nMahanta TG, Boruah M, Singh VK, et al.: Effect of social and behavior change communication by using infotainment in community perception of adolescent girls for reproductive and sexual health care in high priority districts of Assam. Clin Epidemiol Global Health. 2016; 4(3): 133–139. Publisher Full Text\n\nMinistry of Education: Statistics of education, Thailand 2014-2015. 2016.Reference Source\n\nNeranon W, Thongsong L: WN CAIFLS program (version 1.0.0). Zenodo. 2021a, February 13. Publisher Full Text\n\nNeranon W, Thongsong L: Development of a computer-assisted instructional package for life skills to prevent risky sexual behaviors in early adolescents, Bangkok, Thailand.2021b, April 26. Publisher Full Text\n\nOlanratmanee B: Sexuality education for early adolescents: A review of literature. Thai J Nursing Council. 2018; 33(3): 67–81.\n\nPaknoi J, Krungkripetch N, Homsin P: Effects of life skills enhancement program on perceived self-efficacy and outcome expectancy to avoid sexual risk behaviors among female lower secondary school student. J Nursing Health Care. 2017; 35(3): 58–68.\n\nPhumjuntuk A, Duangsong R: The effectiveness of health education program by the application of life skill education and social support for sexual prevention before premature age among the 6th grade students in Nakhonratchasima Province. KKU Res J (GS). 2011; 11(4): 55–66.\n\nPrabmeechai S, Rueangworaboon S: The effects of sex education learning program on sexual knowledge and satisfaction with the program of high school students. Srinagarind Med J. 2017; 32(3): 263–268.\n\nRatta S, Arunwong R, Nithakorn R: The model development of prevention and solution in premature pregnancy of teenages in Kamphaengphet Provice. Humanities Social Sciences J Graduate School. 2015; 9(2): 142–160.\n\nSangchart E, Duangsong R: The effects of health education program with electronic media (facebook) on skill development for adolescent pregnancy prevention among grade 7 students. Journal of the office of ODPC 7 Khon Kaen. 2016; 23(1): 96–104.\n\nSasinun P, Kanakpitch W, Panisara L: Effects of skill development for prevention of sexual risk behavior on precieved self-efficacy and sexual risk behavior among female adolescent. Nursing J. 2013; 40(1): 68–79.\n\nSirited P: Life skill improvement and the prevention of adolescent risky sexual behaviors. J Royal Thai Army Nurse. 2018; 19(2): 10–15.\n\nSirited P: Effect of life-skills development program on the prevention of sexual-risk behaviors in early adolescents. UBRU J Public Health Research. 2019; 8(2): 123–132.\n\nSukpom T, Wichinaowaratana S, Asawasripongtorn K: The development of an instuctional model on giving guidance to make the secondary school students in Chainart Restrain their desire to have premature sex. J Social Science,MCU. 2017; 6(4): 189–202.\n\nThamrongsotthisakul W: The reflection on the concepts of instructional package, learning activity package and learning package. J Education Naresuan University. 19(3): 356–369.\n\nThiammok M, Saranrittichai K: The developmental guidelines to prevent adolescent sexual risk behaviors in community. J Boromarajonani College of Nursing Bangkok. 2017; 33(3): 38–46.\n\nUnite of children: Situation analysis on adolescent pregnancy in Thailand. 2015.Reference Source\n\nVatanasomboon P, Pekalee A, Powwattana A, et al.: Evaluating adoption of a life-skill instructional cartoon by the opportunity expansion schools network with the Thai health promotion foundation. J public health. 2018; 48(1): 57–70.\n\nWidman L, Choukas-bradley S, Helms SW, et al.: Adolescent Susceptibility to Peer Influence in Sexual Situations. J Adolesc Health. 2016; 58(3): 323–329. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWongjunthong K, Rachawijit J: The effects of learning achivement on topic of sex education of Mathayom two students with computer-assistied instruction. J Education Graduate Studies Res. 2010; 4(3): 8–14.\n\nWorld Health Organization: Life skill education for children and adolescents in school. Geneva: Switzerland: 1994."
}
|
[
{
"id": "86597",
"date": "21 Jun 2021",
"name": "Saowaluck Settheekul",
"expertise": [
"Reviewer Expertise Health promotion and sexual 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 research and development study presents how to develop and evaluate CAIFLS among adolescents. Overall, the presentation is well structured, and the discussion part is well balanced and covers the life skills aspects. A few more points may be discussed:\nThe introduction started talking about adolescent pregnancy rates and its consequences and continued with the importance of life skills to prevent risky sexual behaviours. So, there needs to be more explanation about adolescent sexual risk behaviours in Bangkok and Thai cultural norms related to sexual risk behaviours.\n\nMethods - Authors should explain more about the contents and activities of each CAIFLS's lessons, especially the content related to risky sexual behaviours and how role-playing was performed, and how researchers observed the participants.\n\nResults - Authors should rewrite results from t-test analysis based on one-tailed hypothesis tests.\n\nThe limitation of Thai cultural norms should be presented because most contents of CAIFLS were developed based on adults' s perspectives that pre-coital or sexual risk behaviours among adolescents are shamed and prohibited.\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? Partly",
"responses": [
{
"c_id": "6863",
"date": "02 Jul 2021",
"name": "Ladaporn Thongsong",
"role": "Author Response",
"response": "Dear Reviewer I am grateful for your guidance. Your guidance is very helpful in our study. We will be happy to modify the work according to your suggestions. Best regards."
},
{
"c_id": "7634",
"date": "11 Jan 2022",
"name": "Ladaporn Thongsong",
"role": "Author Response",
"response": "The revised part as suggested by reviewer 1 We have revised the paper based on the suggestions from reviewer 1. The revised part as suggested by reviewer 2 The introduction: explains more about the risky behavior of adolescents in Bangkok, and explain Thai cultural norms about risky sexual behavior. The methods: explains more about the contents in topic CAI lesson series entitled Adolescents and life skills on sexual self-prevention, and activities of each CAIFLS’s lessons in topic Data collection. Added lesson plans in Extended data and updated DOI in the new version. Results: I rewrote results from t-test analysis base on hypothesis test. Conclusions: I added the limitation of Thai cultural norms accordingly reviewer's suggestion."
}
]
},
{
"id": "95357",
"date": "28 Sep 2021",
"name": "Christopher Fuster Bueno",
"expertise": [
"Reviewer Expertise Social Science",
"Education and Public Administration"
],
"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\nDevelopment of a computer-assisted instructional package for life skills to prevent risky sexual behaviors in early adolescents, Bangkok, Thailand\nThe study provides a clear and accurate presentation on cited current literature along with the lesson intervention on the computer-assisted instructional package to prevent risky sexual behaviors with positive findings on previous researches. The research design introduces the CAILFS Model to propose and analyze the complementation of the criterion difference on academic achievement and life skills with the use of computer-assisted lesson activities in preventing sexually risky behaviors. It has sufficient details to interpret the factual triangulation of information that can be replicated utilizing the 21st-century teaching-learning strategies on the computer-assisted instructional package with deliberate responsive life skills to prevent risky sexual behaviors.\nThe research replication of the utilization of a computer-assisted instructional package will also enhance the Bloom Taxonomic Model on Higher Order Thinking Skills (HOTS) on effective domain based on the discussion of the life skills. Furthermore, psychomotor and cognitive domains are highly reflective of the computer-assisted instructional packages. It has utilized the descriptive analysis with triangulated analysis on student satisfaction on CAIFLS and used the Kolmogorove-Smirnov Test formula with interesting results on the academic interpretation about the CAIFLS efficacy to prevent risky sexual behaviors. The source of data ensures full reproducibility and the conclusion drawn provides concise results which confirmed the effectiveness of the CAIFLS model applied to the nursing academic community in promoting life skills to prevent risky sexual behaviors.\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": "7271",
"date": "04 Oct 2021",
"name": "Ladaporn Thongsong",
"role": "Author Response",
"response": "Dear Reviewer I am grateful for your guidance. Your guidance is very helpful in our study. Best regards."
}
]
}
] | 1
|
https://f1000research.com/articles/10-385
|
https://f1000research.com/articles/10-490/v1
|
22 Jun 21
|
{
"type": "Research Article",
"title": "Experimental-analytical approach to assessing mechanosensitive cartilage blood marker kinetics in healthy adults: dose-response relationship and interrelationship of nine candidate markers",
"authors": [
"Simon Herger",
"Werner Vach",
"Anna-Maria Liphardt",
"Corina Nüesch",
"Christian Egloff",
"Annegret Mündermann",
"Simon Herger",
"Werner Vach",
"Anna-Maria Liphardt",
"Corina Nüesch",
"Christian Egloff"
],
"abstract": "Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II). Results. COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6. Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.",
"keywords": [
"cartilage biomarkers",
"walking stress test",
"cartilage mechanosensitivity",
"mechanical loading",
"dose-response relationship"
],
"content": "Introduction\n\nPhysical activity is a prerequisite for maintaining a healthy musculoskeletal system. For instance, physical activity in healthy adults reduces the risk of cartilage thinning, cartilage defects, and bone marrow lesions1 although the protective role of joint loading in a physiologic biomechanical and biochemical environment is still controversial2. Moreover, biomechanical risk factors for cartilage degeneration in conditions such as obesity, diabetes (metabolic syndrome), malalignment or trauma with joint injury3 illustrate the central role that mechanical factors can have in an altered biomechanical and/or biochemical setting in osteoarthritis (OA) development and progression4. Although physical activity can relieve OA symptoms5, its role in maintaining healthy cartilage and in the initiation and progression of OA in humans remains largely unknown. Answering the central research question of how living articular cartilage responds to joint loads experienced during daily activities represents a major milestone towards understanding articular cartilage health and if a disruption of this response may play a role in the pathomechanics of OA. Here, we are particularly interested in the acute response to 30 minutes of ambulatory load in healthy individuals.\n\nGenerally, physiologic magnitudes of mechanical loading suppress the proinflammatory and catabolic effects of interleukin (IL)-1, while injurious magnitudes of loading activate proinflammatory and catabolic pathways leading to cartilage degradation6. For instance, dynamic compression of articular cartilage explants at physiologic magnitudes blocks IL-1-induced increases in the mRNA levels of the degradative enzymes A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, matrix metalloproteinase (MMP)-1, MMP-37 and aggrecan break-down8. In the same experimental set up, metalloproteinase inhibitor (TIMP)-3 expression increased. These results suggest a net decrease in MMP activity under these conditions7. In ex vivo experiments, the expression of MMP-1, MMP-3, MMP-8 and MMP-13 significantly decreased in articular cartilage with loads below 0.5 N and the expression of MMP-1 and MMP-13 significantly increased with loads of 1 N9. Moreover, load reduced MMP-1 and MMP-3 synthesis in situ in healthy but not in OA human cartilage suggesting that MMPs play a key role in regulating the balance of structural proteins of the articular cartilage matrix according to local mechanical demands10. Similarly, excessive and continuous cyclic mechanical stress induced load-dependent production of MMP-9 in cultured chondrocytes11. Similar observations have been later reported by Nakyama et al.12. In vivo, increases in IL-6, tumor necrosis factor (TNF)-α, and MMP-9 were greater after a marathon than after a half-marathon13.\n\nCartilage oligomeric matrix protein (COMP) is a prominent constituent of articular cartilage14. Serum concentrations of COMP fragments are elevated in patients with knee OA15 and decrease during immobilization in healthy persons16. Patients with greater serum COMP concentration experience a faster progression of the disease17. It has been suggested that COMP molecules are important for maintaining the properties and integrity of the collagen network18, contribute to the material properties of biological tissue19, and transfer forces from the cartilage matrix to the cell20. Thus, COMP may be an indicator for the relationship between mechanical loading of articular cartilage and biological or pathogenic processes. COMP is upregulated following cyclic compression in situ20, and results of in vivo studies21 in competing marathon runners suggested that mechanical variations in the way individuals perform the same activity are related to the differences in serum COMP levels.\n\nType II collagen is a major articular cartilage constituent, representing 90 to 95% of its total collagen content and forming the fibrils that give cartilage its tensile strength. In the process of collagen fibril formation—which is enhanced in OA cartilage22—the C-propeptide is removed from the procollagen extracellularly and directly reflects the rate of type II procollagen synthesis (CPII)22. Cleavage of type II collagen by collagenases is also excessive in OA cartilage23. It yields fragments such as the COL2−3/4Clong mono epitope (C2C)24 reflecting degradation. A smaller synthesis/degradation (CPII/C2C) ratio has been associated with an increased odds ratio for OA progression25,26 and this ratio increased after load-modifying joint distraction reflecting cartilage regeneration27. Proteoglycan 4 (PRG-4) or lubricin is a proteoglycan that in humans is encoded by the PRG-4 gene and highly expressed by superficial zone chondrocytes and synoviocytes28. PRG-4 is critical for maintaining appropriate boundary conditions of articulating joint surfaces (low friction). In anterior cruciate ligament transected joints in rats, joint exercise and hence load decreased PRG-4 cartilage expression, increased cartilage degeneration and reduced superficial zone chondrocyte viability29. PRG-4 plasma levels in patients with advanced knee OA are lower than in healthy controls30. In recent systematic reviews, COMP, MMP-1 and -3, C2C, and IL-6 were among the most promising prognostic biomarkers for knee OA31–33. Moreover, pre-operative ADAMTS-4 synovial fluid levels predicted outcome in patients with knee OA after high-tibial osteotomy, a load altering joint preserving surgical intervention34. Serum ADAMTS-4 was elevated particularly in patients with early OA and genes associated with ADAMTS-4 participate in collagen metabolism35. Hence, these blood markers are potential surrogates of biological processes in human articular cartilage and involved in OA pathophysiology.\n\nJoint load as experienced during ambulation translates to hydrostatic pressure and compressive, tensile, and shear forces in the extracellular matrix that are transduced to the chondrocyte36,37 resulting in altered turnover of matrix constituents via changes in signaling and regulation of catabolic and anabolic enzymes38,39. In vivo assessment of these interactions in human articular cartilage can only be made by measurements of surrogates of cartilage metabolism (blood markers and urine markers) and estimations of ambulatory load. Several studies16,21,40–44 have investigated the effects of ambulatory exercises (walking, running, marathon and ultramarathon) or immobilization on blood levels of candidate surrogates for cartilage metabolism. All previous studies reported biomarker kinetics during and up to at least 1 hour after the exercise bout. Based on the literature on exercises of varying intensity, one would expect that greater ambulatory load would result in greater biomarker response. However, to date the dose-response relationship between the magnitude of ambulatory load and serum kinetics of mechanosensitive blood markers in vivo in humans is unknown. The purpose of this study was to determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. We conducted an ambulatory loading experiment with repeated blood sampling with three different ambulatory load magnitudes and applied a two-stage analytical approach (Figure 1) for determining the suitability of each of nine potentially mechanosensitive markers (COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C, CPII/C2C and IL-6) for quantifying this dose-response relationship. We hypothesized that some but not all candidate markers would show a dose-response relationship and that the biomarker kinetics in response to load and the dose-response relationship would correlate among mechanosensitive markers.\n\nThe approach comprised two stages consisting of a criterion (I and II, blue), statistical analysis of experimental data (grey) and criteria testing (white) for determining the suitability of each of nine potentially mechanosensitive markers for quantifying the dose-response relationship between ambulatory load magnitude and serum kinetics of mechanosensitive markers.\n\n\nMethods\n\nThis study is an extension of our previously published study on the dose-response relationship between physiological stress and serum COMP levels in healthy subjects45. We combined an experimental approach and an analytical approach as illustrated in Figure 1.\n\nParticipants. Twenty-four healthy persons volunteered to participate in this study (12 female, mean ± standard deviation, age: 25.7 ± 1.4 years; body height: 1.67 ± 0.09 cm; body mass: 62.7 ± 8.4 kg; body mass index (BMI): 22.3 ± 1.6 kg/m2; 12 male, age: 25.0 ± 2.2 years; body height: 1.81 ± 0.08 cm; body mass: 79.1 ± 11.6 kg; BMI: 24.0 ± 2.7 kg/m2). Participants were recruited from July to September 2017 from the local community via advertisement on the institutional website until the desired numbers were reached. Only persons meeting the following inclusion criteria were considered: age between 18 and 30 years; physically active (>2 times/week); BMI below 30 kg/m2; and no previous lower extremity injury and neuromuscular conditions that could have affected their gait. The study was approved by the regional ethics board (Ethikkomission Nordwestschweiz; EKNZ 2017-01006), registered at clinicaltrials.gov (NCT03455010) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to participation.\n\nExperimental design. We used a block randomized crossover design as implemented in our previous study45. Conditions were block randomized by the project manager in two blocks of all possible condition orders per sex to prevent a potential systematic condition effect (Figure 2). Participants were enrolled by the project manager. Sealed envelopes were drawn from a container (one container per block) by the tester. Blinding to the experimental condition was not possible because of the obvious differences between conditions (partial weight bearing and additional load). However, the person processing the data was blinded to the condition. Because it does not seem feasible that a subject can actively alter the load-induced changes in blood markers of articular cartilage, it was assumed that this approach is appropriate for answering the research questions.\n\nParticipants completed a 30-minute walking stress test (hereafter termed ‘stress test’ on a treadmill (mercury® 3p, h/p/cosmos sports & medical GmbH, Nussdorf-Traunstein, Germany) on three different days at the Functional Biomechanics Laboratory, Department of Orthoapedics and Traumatology, University Hospital Basel, Switzerland. One of three ambulatory loads was applied per day: normal body weight (BW) (100% BW = normal load); reduced body weight (80% BW = reduced load); increased body weight (120% BW = increased load). An h/p/cosmos airwalk® system (h/p/cosmos sports & medical GmbH, Nussdorf-Traunstein, Germany) was used to dynamically unload the participant’s body during the unloading condition. The participant was placed in a harness connected to a pneumatic pulley system. The system was set to lower the participant’s BW by 20%. For the increased load condition, participants wore an adjustable weight vest (CAPITAL SPORTS Monstervest 20 kg, Chal-Tec GmbH, Berlin, Germany) with adjustable weights (1 kg increments) corresponding to 20% BW that were secured in pockets attached to the front and back of the vest. The amount of unloading and additional loading during the experiment was confirmed by measurements of the instrumented treadmill as previously described45,46.\n\nFor each participant, the schedule of test days was standardized, and only the load condition was modified. The different loading conditions were tested at the same time of day on three different days interspersed by at least one rest day. No sports or running and moderate to strenuous activities were allowed during the 24 h prior to each appointment. On each test day, participants fasted 1 h before and during the entire experiment. Five blood samples were obtained by venipuncture: 30 minutes before the stress test (t-1); immediately before the stress test (t0); immediately after the stress test (t1); 30 minutes after the stress test (t2) and 60 minutes after the stress test (t3).\n\nParticipants remained seated for 60 minutes before and for 60 minutes after the stress test. Each participant walked for 1 minute on the treadmill while the treadmill speed was continually increased to determine their individual preferred walking speed that was recorded and used for all stress tests for this participant. Then, the participant stood next to the treadmill while the weight vest or unloading harness was adjusted. During the stress test, participants walked on the treadmill for 30 minutes at their predetermined individual preferred speed. Immediately after the stress test, participants returned to their seated position.\n\nBlood samples. Venous blood samples were taken from the antecubital vein. A vein catheter (Vasofix® Safety PUR 20G, B. Braun Melsungen AG, Melsungen Germany) was placed during the rest period before the first blood sample at t-1 using sterile, disposable equipment and secured by tape. The catheter remained in the vein for 2.5 h. After every blood sample, the catheter was flushed with 10 ml isotonic saline solution (0.9% NaCl) to prevent plugging by clotting blood. The first 3 ml of each sample were discarded to avoid dilution through the injected saline solution. The blood samples clotted in the blood tubes (S-Monovette® 7.5ml Z-Gel, Sarstedt AG, Nürnbrecht, Germany) for 30 minutes. Subsequently, they were centrifuged (Sarstedt AG &Co SMC6) for 15 minutes at 2016 g, separated into aliquots and frozen (-20°C). The tubes were transferred to a -80°C freezer within 48 h until assayed.\n\nSerum biomarker levels were measured using commercial enzyme-linked immunosorbent assays (Human COMP protein ELISA kit, BioVendor, Modrice, Czech Republic; Human Total MMP-3 and MMP-9 Immunoassays, R&D Systems Inc., Minneapolis, USA; Human Proteoglycan 4 (PRG-4) ELISA Kit, CUSABIO Technology LLC, Houston, USA; Human ADAMTS-4 ELISA Kit, Sigma-Aldrich, Saint Louis, USA; Human IL-6 Immunoassay, R&D Systems Inc., Minneapolis, USA; Human C2C and CPII ELISA kits, IBEX Pharmaceuticals Inc., Montréal, Canada). All samples were analyzed in duplicates. Intra-assay variability was estimated as coefficient of variation between the duplicates and were 2.2 ± 2.0% for COMP; 2.6 ± 1.7% for MMP-3; 1.2 ± 1.1% for MMP-9; 1.3 ± 1.3% for ADAMTS-4; 4.8 ± 3.8% for PRG-4; 2.4 ± 2.7% for IL-6; 8.1 ± 6.5% for C2C; and 3.0 ± 2.7% for CPII. The mean of the duplicates for each time point and condition was used for further analysis. The ratio between CPII and C2C was considered as an additional biomarker of synthesis/degradation24,25. The ratio was defined as the inverse of the ratio considered in the original publication because we expected a stimulation of tissue synthesis in a healthy population in response to a stress test (CPII:C2C – synthesis/degradation).\n\nWe defined a series of criteria to depict the suitability of a mechanosensitive biomarker (Figure 1). Criterion I focused on the question of whether the biomarker responds to the stress test and was phrased as two questions:\n\nIa) Is there on average a response to the walking exercise for at least one of the three post-stress test time points?\n\nIb) Is there an inter-individual variation in the response to the walking exercise for at least one of the three post-stress test time points?\n\nIf at least one of these two questions was answered with ‘yes’, the dependence of the magnitude of the response on the magnitude of load was analyzed for any time point the criteria was fulfilled.\n\nThe dependence of the magnitude of the response of the biomarkers on the magnitude of the load was addressed at the individual level. Within each individual, we investigated at each time point how the response changes with the load by considering the slope of a regression line through the three points defined by the three ambulatory load levels (80% BW, 100%BW and 120%BW) (on the x-axis) and the magnitude of the response (on the y-axis). Consequently, Criterion II addressed the questions:\n\nIIa) Is there on average a slope different from 0?\n\nIIb) Is there an inter-individual variation in this slope?\n\nIf at least one of these two questions was answered with ‘yes’ for a specific biomarker at least one time point, then this biomarker was regarded as suitable for assessing the dose-response relationship between ambulatory load magnitude and biomarker kinetics in response to load. Note that question IIa answers also the question about a relation of the response to the magnitude of load at the population level because an average slope of 0 is equivalent to no trend in the load level specific mean response values at the population level.\n\nIf we can establish the suitability of several biomarkers using this approach, the natural question arises whether each biomarker can provide independent information or whether the different biomarkers measure the same. We hence also investigated the correlation of the individual changes and the individual slopes, respectively, between the different biomarkers.\n\nWe investigated the impact of the stress test and the load on the biomarker kinetics by considering the change from the baseline measurements at t0. Both the change in the absolute and the relative biomarker concentrations were considered, as it could not be decided a priori which type of concentration is more relevant. We used definitions trying to minimize potential drawbacks of absolute respective relative concentrations. For the absolute changes we used\n\nwhere yt denotes the concentration at the time points t1, t2, and t3, y0 the concentration at t0, and m denotes the median value of the raw measurements at baseline (t0) (over all load levels and subjects) for the marker. Therefore, we can interpret the change in relation to the median value, and, for instance, a five-point change means that we observe a change corresponding to 5% of the median value. This way the absolute changes become comparable across the markers.\n\nFor the relative changes we shifted all measurements by a constant amount c, i.e. we used the formula\n\nThe constant c is chosen such that the maximal relative change at the time points t1 and t2 overall load levels is limited to 75%. This way we diminish the instability of relative changes when y0 approaches 0.\n\nTo assess the investigated the impact of the stress test and the load on the biomarker concentration at a specific timepoint t > 0, the change measurements δil for the individual i at load level l (with l coded as -1, 0 and 1) are modeled as\n\nsuch that αi reflects the response to the stress test (at load level 100%) of individual i and βi the dependence on the load for individual i. These individual models were then combined into an overall mixed model assuming that the intercepts αi and the slopes βi are drawn from a bivariate normal distribution. The mean μα and the standard deviation σα of the intercepts reflect the average response to the walking exercise and the inter-individual variation in this response. The mean μβ and the standard deviation σβ of the slopes reflect the average dependence of the response on the load and the inter-individual variation in this dependence. Fitting such a mixed model provides us with estimates for these four quantities. In fitting the models, we used the restricted maximum likelihood techniques. P-values for the standard deviation were based on a likelihood ratio test using a mixture of two χ2 distributions as reference, as suggested by Self and Liang47.\n\nA choice of μα = σα = μβ = σβ = 5 would reflect a situation of clinical interest. Based on 1000 simulations from the model we can conclude that we have a power of 98%, 87%, 98%, and 78%, respectively, to detect a difference from 0 at the 5% for each of the four parameters, if the standard deviation of the error term is 5. In the case of a standard deviation of 7, the power reduces to 96%, 54%, 93%, and 44%. Hence the chosen sample size of 24 is sufficient to declare markers of clinical interest as suitable with respect the average response or the average load, and also sufficient to detect inter-individual variation if the error variation is not too high.\n\nWith respect to the correlation between the biomarkers identified as suitable, we first considered the correlation in the individual changes. We try here to summarize the information from all three load levels by computing first the Spearman correlation at each load level and then taking the average. Inference for these average correlations was based on using the bootstrap and a normal approximation after applying Fisher’s z-transformation. In a second step we considered the correlation between the slopes. Here we computed the slope within each individual and reported the Spearman correlation.\n\nAll statistical computations were performed with Stata 15.1 (StataCorp LLC, College Station, TX, USA). All computations can also be performed in R (The R Foundation, Vienna, Austria). The level for statistical significance was set a priori to 5%.\n\nThis study was approved by the regional ethics committee (Ethikkommission Nordwestschweiz EKNZ 2017-01006).\n\nWritten informed consent for participation and for publication of the participants details was obtained from all participants.\n\n\nResults\n\nRaw measurements can be inspected at 48. Many parameters showed a substantial variation in resting levels between subjects. For ADAMTS-4, high intra-individual variation required the use of a logarithmic scale to visualize the data. In subject 110, the values of ADAMTS-4 fluctuated much more than in all other participants and were outside the detection limits, and hence we excluded this subject from the analysis of ADAMTS-4. For COMP, MMP-3 and IL-6, we observed a clear pattern in the response to the walking stress test over time, which was rather uniform across load levels and individuals. While for MMP-9, PRG-4 and ADAMTS-4, there were still similarities in the patterns across load levels at least for some individuals, for C2C, CPII and the CPII to C2C ratio, there appeared to be no common patterns.\n\nRaw values were transformed to change values as described in the Methods sections. However, for ADAMTS-4, the absolute changes were based on log-transformed values (log10(1+x)) instead of the raw values.\n\nAverage response and inter-individual variation in response to walking exercise. Mean values of relative load-induced changes at all loads and all time points are shown in Figure 3. Individual and mean trajectories of the relative load-induced change of each biomarker are shown in Figure 4. Table 1 summarizes the evidence from this data on average response and inter-individual response variation. We observed a distinct average response to the stress test for COMP at t1 and t2 and for MMP-3 and IL-6 at all three time points after the stress test. For both COMP and MMP-3, we observed an average relative increase above 25% at t1. For COMP we observed a subsequent rapid decline to an average of about 5% at t2 and close to 0% at t3. For MMP-3, the decline was slower with an average of 13% at t2 and 4% at t3. For IL-6 we observed an increasing trend from an average increase relative to baseline of 6% at t1 to 9% at t2 to 21% at t3. There was some evidence for an average response for CPII and ADAMTS-4 at t1, but with rather low levels of less than 5% relative change. There was a significant average response for PRG-4 at t2, but because the average change was negative and not in agreement with the averages at the other two time points, we regarded this as a spurious finding. There was rather clear evidence for inter-individual response variation in COMP and MMP-3 at all time points and for IL-6 at t2 and t3. For COMP and MMP-3 the magnitude of the variation was similar with standard deviations of about 10% at t1 decreasing over time to about 5% at t3. For IL-6 the variation increased over time from about 5% at t1 to about 20% at t3. Interestingly, we also observed an inter-individual response variation for MMM-9 at time points t2 and t3, although there was no evidence for any average response. Considering absolute changes instead of relative changes lead to similar results (Table 2), except that the inter-individual variation for MMP-9 lacked significance and PRG-4 showed a negative response at all time points.\n\nValues above 100 and below 50 are truncated and marked with a triangle or a square, respectively. COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; PRG—proteoglycan; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; C2C—COL2−3/4Clong mono epitope; CPII—rate of type II procollagen synthesis.\n\nCI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; PRG—proteoglycan; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; C2C—COL2−3/4Clong mono epitope; CPII—rate of type II procollagen synthesis.\n\nCI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; PRG—proteoglycan; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; C2C—COL2−3/4Clong mono epitope; CPII—rate of type II procollagen synthesis.\n\nIn summary, taking into account the criteria Ia and Ib stated in the Methods section, COMP, MMP-3 and IL-6 at all three post stress time points, MMP-9 at time point t2 and t3, and ADAMTS-4 and CPII at t1 were generally sensitive to the stress test and considered suitable mechanosensitive markers according to criterion I. All further investigations were hence restricted to these marker/time point combinations.\n\nAverage slopes and inter-individual variation in slopes describing the dose-response relationship. When considering the relation between the magnitude of load and the response for the selected parameter/time point combination in Table 3, we observed for MMP-3 an average slope clearly above zero for all time points. The relative change in MMP-3 increased by 8% from load level to load level (low – medium – high) at t1, and by 6% and 4% at t2 and t3, respectively. The relative change in COMP increased by five percentage points from load level to load level (low – medium – high) at t1 without a distinct increase at later time points. For all other parameters, there was little evidence for an average slope different from zero with estimates of the increase of less than 2.5 percentage points in absolute values. There was, however, some evidence for inter-individual variation in the slopes. This did not only hold for COMP and MMP-3 with standard deviations in the magnitude of three to four percentage points reaching significance at some time points but also for MMP-9, ADAMTS-4 and CPII with estimated standard deviations between five and 15 percentage points reaching also partially statistical significance. These insights were also corroborated when inspecting the individual data included in these computations (Figure 5), indicating the existence of participants with nearly no change in response over the different load levels, participants with an increasing response from lowest to highest load, and participants with a decreasing response. The results with respect to the inter-individual variation were less clear for IL-6 with possible variation at t1. When considering the absolute changes (Table 4 and Figure 6), we observed very similar results.\n\nCI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nCOMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nCI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nCOMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nCorrelations among relative change variables. Table 5 and Figure 7 depict the correlations among the relative change variables that satisfied the criteria for a suitable marker. As expected, we observed substantial correlations among the change variables for the same marker at different time points except for the change in IL-6 at t1 and t3. The cross-marker correlations were generally rather low (|R| < 0.2) with the exception of the correlations between COMP and MMP-3 at the same time point but also across time points, and correlations between ADAMTS-4 at t1 and MMP-3 at all time points. A similar pattern was observed for the absolute change (Figure 8).\n\nShown are the estimated Spearman correlations (averaged over the three load levels). p-values are given in italics.\n\nShown are the estimated Spearman correlations (averaged over the three load levels). p-values are given in italics. CI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis. Correlations above 0.25 or below -0.25 are marked in bold.\n\nShown are the estimated Spearman correlations (averaged over the three load levels). COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nShown are the estimated Spearman correlations (averaged over the three load levels). COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nTable 6 and Figure 9 depict the correlations between the slopes based on the relative change. Again, we observed substantial correlations among the slopes for the same marker at different time points (contributing also to the conceptual validation of the slopes). Cross-marker correlations were again often low (|R| < 0.2), but we did not only observe some correlation between the slopes of COMP and MMP-3, but also a negative correlation between the slopes of COMP and MMP-9 (also across time points), and – to a lower degree – between the slopes of MMP-3 and MMP-9. Negative correlations were also observed between the slopes of IL-6 on one side and the slopes of COMP and MMP-9 on the other side at some time points. A similar pattern was observed for the slopes based on the absolute change (Figure 10).\n\nShown are the estimated Spearman correlations. p-values are given in italics, correlations with p-values below 0.05 in bold.\n\nShown are the estimated Spearman correlations. p-values are given in italics. CI—confidence interval; SD—standard deviation; COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis. Correlations above 0.25 or below -0.25 are marked in bold.\n\nShown are the estimated Spearman correlations. COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nShown are the estimated Spearman correlations. COMP—cartilage oligomeric matrix protein; MMP—matrix metalloproteinase; ADAMTS—A disintegrin and metalloproteinase with thrombospondin motifs; IL—interleukin; CPII—rate of type II procollagen synthesis.\n\nIn summary, COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 fulfilled criterion II for assessing the dose-response relationship between ambulatory load magnitude and biomarker kinetics.\n\n\nDiscussion\n\nThe aim of this study was to determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. We identified several promising markers. COMP seems to be able to reflect a rapid response to physiological stress, while MMP-3 seems to show a slightly longer lasting but also more distinct (greater and more consistent) response. MMP-3 showed also the strongest association with the magnitude of load. The metabolic response measured by IL-6 is also clearly long lasting, probably beyond the time span covered in our set up. Interestingly, this might also be the case for MMP-9, for which we could not observe a response on average, but nevertheless inter-individual variations of the changes and slopes at the late time points. For ADAMTS-4 and CPII, we also found signs of an inter-individual variation in the relation of the magnitude of load to the response at t2. These results strongly indicate that assessing one isolated biomarker in the context of loading (and unloading) experiments may not fully capture the metabolic dynamics in response to load. Moreover, it is possible that there are responders and non-responders to physiological stress or that the response is affected by factors such as disease or injury, which we did not investigate in this study.\n\nThe results of our experiment and analytical approach represents an extension of previous reports of changes in blood biomarker levels with load during physical activity, immobilization, and microgravity. For instance, previous studies21,40–43 have investigated the effects of walking, running, marathon and ultramarathon on blood levels of candidate surrogates for cartilage metabolism, most prominently on COMP. Walking for 30-minutes increased serum COMP levels in young healthy adults49, in older healthy adults and in patients with knee OA50. The dynamics of COMP after the exercise appeared to differ between these groups50. Niehoff et al.41 observed a 39% increase in COMP immediately after running for 30-minutes that remained elevated for up to 90 min after the running intervention before returning to the baseline level. In contrast, deep knee bends or lymphatic drainage did not elicit any changes in COMP levels. Neidhart et al.40 reported that during a marathon run, serum levels of IL-1RA, IL-6, TNF-α and COMP rose significantly, and gradually returned to baseline within 24 h. In another marathon study, differences in serum levels from before to after the run were observed for COMP, IL-6 and hsCRP but not for TNF-α43. Mündermann et al.42 found elevated COMP, MMP-9 and MMP-3 but not in MMP-1, C2C, CPII, and C2C:CPII throughout a multistage ultramarathon (4486 km). Interestingly, immobilization during bed rest studies has resulted in decreased levels of COMP, MMP-3, and MMP-9 but not MMP-1 and in elevated TNF-α levels16,51. Moreover, a delayed increase in COMP was observed in astronauts upon return to gravity after six months on the International Space Station52. While some of these studies acknowledged the effect of different loads on blood biomarker dynamics, none of these studies quantified the accumulated load during the physiological stress or unloading condition. In this context, the question arises whether a greater response can be provoked with a higher than normal load and if individuals who are more sensitive to higher loads have subclinical cartilage and/or joint damage.\n\nRemarkably, the mechanosensitive biomarkers identified in this study are biomarkers that are upregulated and mediate cartilage break-down in OA53,54. For instance, Georgiev et al.55 have recently shown that serum COMP and MMP-3 levels were higher in patients with diagnosed knee OA and that patients with more severe knee OA had higher COMP levels than patients with less severe knee OA. These researchers also reported that MMP-3 levels were higher in the generalized OA compared to the isolated knee OA group and suggested that COMP may reflect knee structural damage while MMP-3 may reflect OA “generalization”. Moreover, our results of a correlation between COMP and MMP-3 levels among healthy subjects confirm previously reported55 correlations between these biomarkers across healthy persons and patients with OA. Interestingly, five participants in our study had resting COMP levels above the cut-off value of 717.5 ng/mL (sensitivity 73.2% and specificity 71.0%) to differentiate between controls and patients with knee OA, and one participant after the walking exercise even reached COMP levels above the cut-off value of 1185 ng/mL for OA (100% specificity with 33.9% sensitivity) as reported by Georgiev et al.55. In contrast, MMP-3 levels in all participants were well below the cut-off values to differentiate between controls and patients with knee OA55. This observation suggests that the response in MMP-3 levels to ambulatory load may be more sensitive to exercise in healthy joints than that in COMP levels because none of our subjects had symptoms of OA and we would have not expected levels above the cut-off values for OA. COMP levels above cut-off values also emphasize the need for standardized testing protocols because of the mechanosensitivity of the markers and hence that loading can result in increased values in healthy individuals that are in the range of OA.\n\nTo the best of our knowledge, this is the first study to show changes in serum ADAMTS-4 depending on the load magnitude in vivo in humans. ADAMTS-4 is induced by IL-6 and cleaves COMP56. High loading regimen (high stress, excessive duration) have been shown to increase ADAMTS-4, and aggrecan degradation in human articular cartilage explants is mediated by ADAMTS-457. Moreover, genes associated with ADAMTS-4 participate in collagen metabolism35. The results of our study suggest that load experienced during daily activities may be sufficient to influence metabolic pathways and transport of markers, and hence may play a role in maintaining healthy articular cartilage and potentially in degenerative processes in OA. Moreover, slight modifications in the load magnitude such as when wearing a backpack seem to have a profound effect on the response of the tissue to the exercise. In a mechanical loading experiment on articular cartilage explants, Schätti et al.58 showed that sliding loads that increase extracellular matrix deformation/strain induce enzyme-mediated catabolic processes in articular cartilage explants reflected by increased ADAMTS-4 (and MMP-3) gene expression. Hence, the combination of modified load magnitude with situations of joint instability such as after rupture of the anterior cruciate ligament may be particularly precarious for initiating or accelerating degenerative processes leading to premature OA.\n\nInterestingly, IL-6 responded to the physiological stress but did not show a dose-response relationship in our study, yet we observed correlations between IL-6 and COMP and MMP-3 after loading suggesting that IL-6 may play an important role in the context of mechanosensitivity of articular cartilage biomarkers. In general, IL-6 levels increase exponentially after strenuous exercise, and the magnitude of the increase depends on the length and intensity of the exercise59. Even a walking exercise – although with walking distances beyond 30 km per day – may result in a 40-fold increase in IL-6 levels60. While several studies have reported a peak in IL-6 levels at the end of an exercise61–63, in our experiments IL-6 increased exponentially after completing the exercise. IL-6 is produced locally in the skeletal muscle in response to exercise64, and the IL-6 produced by contracting skeletal muscle may partly mediate exercise-related metabolic changes65. Consequently, the lack of a distinct relationship between load magnitude and IL-6 levels suggest that the different loading conditions did not represent relevant differences in the demand on skeletal muscle further supporting our experimental framework of altering joint load without substantial changes in exercise intensity. We observed a large variability in increase in IL-6 in response to the walking exercise among subjects. This result is surprising because a 30-minute walking exercise at self-selected speed – whether with 20% lower or 20% greater body weight – in physically active healthy persons would be expected to be of similar intensity for all participants. However, in the current study we did not assess any parameters describing the associated cardiovascular stress such as heart rate or oxygen saturation, and hence this variability warrants further investigation.\n\nIn this study, we assessed the suitability of different biomarkers for assessing the dose-response relationship between ambulatory load and load-induced change in biomarker levels by looking at their increase relative to the pre-test values. Similarly, previous studies21,40–43 have focused on assessing load-induced increases in candidate biomarkers. However, whenever we observe an initial increase, the response of the biomarker to the stress test is not only given by this increase but also by the subsequent decline, which may occur at a different rate. COMP and MMP-3 showed rather uniformly such an initial increase. We can observe in Figure 4 that this decline is again rather uniform and tends to compensate the initial increase. Hence, by analyzing this decline, we observed roughly the same results as when analyzing the initial increase (data not shown). It might be of interest to analyze also deviations from this general pattern to compensate the initial increase by looking at residuals from a corresponding prediction model, but this approach would require larger sample sizes. Therefore, assessing not only the variability in specific biomarker dynamics in response to a specific loading condition, but also the dependency of these dynamics to the load magnitude may be particularly useful for identifying persons who might be particularly sensitive to changes in load or at risk for articular cartilage degeneration.\n\nData obtained with an instrumented knee prosthesis revealed that compressive load at the knee can exceed twice the person’s BW during walking, stair walking, rising from a chair, squatting, and even during a golf swing66, and peak loads during running can be as high as four times those experienced during walking67. However, mechanical load is not only defined by its magnitude but also by the frequency of load application, time between load applications and number of loading cycles. Ambulation comprises different modes ranging from walking to running and sprinting for different durations (seconds to hours) and includes extreme exercises such as multistage ultramarathons. Interestingly, the load per unit distance travelled may be smaller in more demanding modes of ambulation (e.g., running: greater load magnitude and higher cadence but longer time between load application and fewer loading cycles per unit distance travelled) than in less demanding modes of ambulation (e.g. walking)67. Hence, all characteristics of load must be considered when modulating the dose of ambulatory load, and ideally only one characteristics of load (e.g., load magnitude) is modulated while the other characteristics (e.g. cadence, duration) remain constant. As previously reported, we were able to modulate ambulatory load magnitude without relevant changes to loading frequency (cadence), duration, number of steps (constant walking speed across conditions), or joint kinematics in the current experimental setup46.\n\nThe response of biomarkers to an exposure like a stress test is typically assessed by the change in the measured values from pre-stress test to post-stress test at the individual level. However, there are two ways to assess the change: we can consider the absolute change or the relative change compared to the pre-stress test measurements, and both approaches can be found in the literature16,21,40–44. Relative changes have the advantage that they take into account that changes are often roughly proportional to the pre-stress test value. They are also directly comparable across different markers, which is not the case for absolute changes. However, relative changes introduce additional variation and tend to be unstable if the pre-stress test values are close to zero. We investigated both approaches in this paper and used definitions trying to minimize the drawbacks and obtained very similar results. Consequently, our conclusions do not depend on the choice of considering absolute or relative changes.\n\nOverall, we demonstrated that our experimental setup is well suited to study the dependence of the biomarker response to ambulatory activity on the magnitude of load and even the individual variation in the magnitude of load versus response relationship. The latter is in particular corroborated by correlations of the slopes across various markers. Using this experimental framework, we were able to modulate ambulatory load magnitude without any relevant changes in joint kinematics46. Although participants were instructed to refrain from demanding physical activity during the 24 h prior to and from any exercise on the day of the respective experiments, we did not monitor their activity. However, the entire loading experiment (2.5 h) was controlled. As in all human experiments, we were limited to estimating metabolic changes in articular cartilage by assessing systemic changes in serum biomarker levels. Moreover, although we did measure the ground reaction force during all loading experiments confirming the desired loading or unloading46, we were not able to directly measure ambulatory load at the tissue level. In this study, we did not collect imaging data on the study participants to confirm joint health but relied on their self-reported data concerning no injury history. Although at the age of younger than 28 years of age this is very unlikely, we cannot completely rule out the presence of early degenerative changes in all participants. Nonetheless, we believe that our current data set represents a major advance in the area of in vivo in human articular cartilage biomarker mechanosensitivity.\n\nIn this study, we chose to apply a targeted and conservative approach by assessing a set of specific serum markers that had been shown to be relevant for articular cartilage health and degeneration and/or responsive to acute loading using well-established methods (ELISAs). In a next step, the analyses could be expanded to targeted or untargeted metabolomic and proteomic approaches68,69 that may allow to discover novel markers with a possibly even stronger dose-response relationship70. This framework forms the basis for elucidating whether the sensitivity of biomarker kinetics to different ambulatory loads changes with age or is disrupted by joint injury hence evidence of altered cartilage mechanosensitivity in the early stage of OA and for testing pharmacological interventions with using participants as their own controls.\n\n\nConclusion\n\nOur experimental framework and two-stage analytical approach appear well suited for studying the dependence of biomarker kinetics in response to ambulatory activity on the magnitude of load and even the individual variation in the magnitude of load versus response relationship in vivo in humans. We identified COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 as markers that warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load. Interactions among selected marker kinetics in this experimental framework of altering joint load may represent an opportunity for investigating metabolic processes in response to load.\n\n\nData availability statement\n\nZenodo: Kinetics of selected blood biomarkers of articular cartilage in response to stress test with modulated ambulatory load. https://doi.org/10.5281/zenodo.495598248\n\nThis project contains the following underlying data;\n\nraw data.pdf: Raw concentrations for each marker (COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C, CPII/C2C and IL-6), participant, time point and condition.\n\nIt also contains the following reporting guidelines.\n\ntrendstatement_TREND_Checklist_Mundermann.pdf: Completed TREND checklist\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthors’ contributions\n\nAM and SH designed the study; SH recruited the participants, collected the data and processed the blood samples; SH, CN prepared the data for statistical analysis; WV performed the statistical analysis; all authors interpreted the data; AM, WV, AML and CE prepared the manuscript; all authors contributed to reviewing and revising the manuscript, and agreed on the final draft.",
"appendix": "References\n\nRacunica TL, Teichtahl AJ, Wang Y, et al.: Effect of physical activity on articular knee joint structures in community-based adults. Arthritis Rheum. 2007; 57(7): 1261–8. PubMed Abstract | Publisher Full Text\n\nBricca A, Wirth W, Juhl CB, et al.: Moderate Physical Activity and Prevention of Cartilage Loss in People With Knee Osteoarthritis: Data From the Osteoarthritis Initiative. Arthritis Care Res (Hoboken). 2019; 71(2): 218–26. PubMed Abstract | Publisher Full Text\n\nArden N, Nevitt MC: Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol. 2006; 20(1): 3–25. PubMed Abstract | Publisher Full Text\n\nAndriacchi TP, Favre J, Erhart-Hledik JC, et al.: A systems view of risk factors for knee osteoarthritis reveals insights into the pathogenesis of the disease. Ann Biomed Eng. 2015; 43(2): 376–87. 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PubMed Abstract | Publisher Full Text\n\nLi W, Du C, Wang H, et al.: Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages. Genet Mol Res. 2014; 13(4): 9642–9. PubMed Abstract | Publisher Full Text\n\nPhan MN, Leddy HA, Votta BJ, et al.: Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum. 2009; 60(10): 3028–37. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMobasheri A, Barrett-Jolley R, Carter SD, et al.: Functional Roles of Mechanosensitive Ion Channels, ß1 Integrins and Kinase Cascades in Chondrocyte Mechanotransduction. In: Kamkin A, Kiseleva I, editors. Mechanosensitivity in Cells and Tissues. Moscow. 2005. PubMed Abstract\n\nSmith RL, Lin J, Trindade MC, et al.: Time-dependent effects of intermittent hydrostatic pressure on articular chondrocyte type II collagen and aggrecan mRNA expression. J Rehabil Res Dev. 2000; 37(2): 153–61. PubMed Abstract\n\nSmith RL, Rusk SF, Ellison BE, et al.: In vitro stimulation of articular chondrocyte mRNA and extracellular matrix synthesis by hydrostatic pressure. J Orthop Res. 1996; 14(1): 53–60. PubMed Abstract | Publisher Full Text\n\nNeidhart M, Müller-Ladner U, Frey W, et al.: Increased serum levels of non-collagenous matrix proteins (cartilage oligomeric matrix protein and melanoma inhibitory activity) in marathon runners. Osteoarthritis Cartilage. 2000; 8(3): 222–9. PubMed Abstract | Publisher Full Text\n\nNiehoff A, Kersting UG, Helling S, et al.: Different mechanical loading protocols influence serum cartilage oligomeric matrix protein levels in young healthy humans. Eur J Appl Physiol. 2010; 110(3): 651–7. PubMed Abstract | Publisher Full Text\n\nMündermann A, Klenk C, Billich C, et al.: Changes in Cartilage Biomarker Levels During a Transcontinental Multistage Footrace Over 4486 km. Am J Sports Med. 2017; 45(11): 2630–6. PubMed Abstract | Publisher Full Text\n\nMündermann A, Geurts J, Hugle T, et al.: Marathon performance but not BMI affects post-marathon pro-inflammatory and cartilage biomarkers. J Sports Sci. 2017; 35(7): 711–8. PubMed Abstract | Publisher Full Text\n\nLiphardt AM, Mündermann A, Koo S, et al.: Vibration training intervention to maintain cartilage thickness and serum concentrations of cartilage oligometric matrix protein (COMP) during immobilization. Osteoarthritis Cartilage. 2009; 17(12): 1598–603. PubMed Abstract | Publisher Full Text\n\nHerger S, Vach W, Liphardt AM, et al.: Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults. Osteoarthritis Cartilage. 2019; 27(1): 106–13. PubMed Abstract | Publisher Full Text\n\nHerger S, Nüesch C, Liphardt AM, et al.: Framework for modulating ambulatory load in the context of in vivo mechanosensitivity of articular cartilage. Osteoarthritis and Cartilage Open. 2020; 2(4): 100108. 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PubMed Abstract | Publisher Full Text\n\nLiphardt AM, Mündermann A, Koo S, et al.: Relevance of immobility for serum levels of biomarkers for cartilage health. 19th IAA Human in Space Conference 2014; Waterloo, Canada. 2014.\n\nNiehoff A, Dreiner M, Mündermann A, et al.: The effect of micro-and hypergravity on serum comp levels in healthy adults. Osteoarthritis and Cartilage. 2019; 27: S169–S70. Publisher Full Text\n\nSun HB: Mechanical loading, cartilage degradation, and arthritis. Ann N Y Acad Sci. 2010; 1211: 37–50. PubMed Abstract | Publisher Full Text\n\nGoldring MB, Marcu KB: Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 2009; 11(3): 224. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGeorgiev T, Ivanova M, Kopchev A, et al.: Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study. Rheumatol Int. 2018; 38(5): 821–30. 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}
|
[
{
"id": "88074",
"date": "19 Jul 2021",
"name": "Ali Mobasheri",
"expertise": [
"Reviewer Expertise Biomarkers of osteoarthritis and articular cartilage turnover."
],
"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:\nIn this article, the authors determined the suitability of a selected panel of biomarkers as mechanosensitive markers of articular cartilage and investigated the dose-response relationship between ambulatory load magnitude and marker kinetics in response to mechanical joint loading. They found that COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 respond to ambulatory load and they propose that these markers should be further investigated in the context of articular cartilage mechanosensitivity and its role in joint degeneration and osteoarthritis (OA).\nMajor comments:\n\nThis is a well-written and comprehensive manuscript that should be of interest to the readership of F1000 Research. However, a number of important revisions are recommended.\n\nOne of the major challenges associated with the use of commercially available enzyme-linked immunosorbent assays is that they measure the quantity of the protein to which the antibody within the assay was developed. Commercially available kits do not reflect important parameters such as epitopes and biological/enzymatic activity. For example, in the case of MMP-3 (stromelysin), the majority of commercially available kits do not measure active levels of MMP-3. Most of the commercial kits that are commercially available for MMP-3 measure total protein, but in most cases, only a small fraction of MMP-3 is proteolytically cleaved and activated. Therefore, all investigators need to carry out functional studies and estimate the quantity of active MMP-3. The use of commercially available enzyme-linked immunosorbent assays is widespread but unfortunately little biological and mechanistic insight is offered by kits that measure total protein levels. This results in numerous publications that simply talk about protein levels rather than epitopes and activity.\n\nThe authors conclude that COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 are biomarkers that warrant further investigation in the context of articular cartilage mechanosensitivity and the role of cartilage mechanosensitivity in the development of OA.\n\nThe observations that they have made in relation to COMP have been made by Lohmander, Strglics and others in Lund University in the context of joint injury. However key references are missing and have not been cited in this paper.\n\nThe manuscript will benefit from an updated discussion of the role of protein activity (especially relating to matrix metalloproteinases) rather than total protein levels.\n\nA few missing references should be cited as well. (e.g. Dahlberg et al. (19941), Lohmander et al. (19942), Clutterbuck et al. (20113)).\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": "7612",
"date": "11 Jan 2022",
"name": "Annegret Mündermann",
"role": "Author Response",
"response": "Dear Dr. Mobasheri, We would like to thank you for your feedback and your critical comments. We believe that the quality of our manuscript has improved by addressing the comments received. Please find our response to the comments below. Your comments by the reviewers are shown in quotation marks, our responses are shown below each comment in regular font. “This is a well-written and comprehensive manuscript that should be of interest to the readership of F1000 Research.” Thank you. \"However, a number of important revisions are recommended.\" We have addressed all comments as outlined below. “One of the major challenges associated with the use of commercially available enzyme-linked immunosorbent assays is that they measure the quantity of the protein to which the antibody within the assay was developed. Commercially available kits do not reflect important parameters such as epitopes and biological/enzymatic activity. For example, in the case of MMP-3 (stromelysin), the majority of commercially available kits do not measure active levels of MMP-3. Most of the commercial kits that are commercially available for MMP-3 measure total protein, but in most cases, only a small fraction of MMP-3 is proteolytically cleaved and activated. Therefore, all investigators need to carry out functional studies and estimate the quantity of active MMP-3. The use of commercially available enzyme-linked immunosorbent assays is widespread but unfortunately little biological and mechanistic insight is offered by kits that measure total protein levels. This results in numerous publications that simply talk about protein levels rather than epitopes and activity.” Response: The reviewer raises an important point. We have added this aspect as a limitation in the Discussion section and proposed that the current samples could be exploited in future analyses targeting epitopes and activity to offer further biological and mechanistic insight into the effect of well-defined mechanical stimuli on articular cartilage biology. “The authors conclude that COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 are biomarkers that warrant further investigation in the context of articular cartilage mechanosensitivity and the role of cartilage mechanosensitivity in the development of OA.” No response is required. “The observations that they have made in relation to COMP have been made by Lohmander, Strglics and others in Lund University in the context of joint injury. However key references are missing and have not been cited in this paper.” Response: We are aware of the previous studies on biomarkers in OA and injury and we now cite the stated reference in the introduction section. However, in our study, we focused on the dose-response relationship of load-induced blood marker concentrations and ambulatory load mechanics. No previous study has addressed this topic in patients with osteoarthritis or after injury. We will address this point in a currently ongoing trial. “The manuscript will benefit from an updated discussion of the role of protein activity (especially relating to matrix metalloproteinases) rather than total protein levels.” Response: We agree that this is an important point. However, because the focus of our study was the dose-response relationship of load-induced blood marker concentrations and ambulatory load mechanics and we did not assess protein activity. Since we cannot provide data showing that protein activity depends on load magnitude, we believe that discussing this aspect is not within the scope of this manuscript. However, depending on available funding, we will pursue additional analyses on protein activity. “A few missing references should be cited as well. (e.g. Dahlberg et al.(19941), Lohmander et al. (19942), Clutterbuck et al. (20113)).” Response: Thank you for providing these references. We have added these references in the context of biomarkers and OA respective joint injury in the Introduction section and in the context of the potential of future analyses using targeted or untargeted metabolomic and proteomic approaches in the Discussion section."
}
]
},
{
"id": "93903",
"date": "21 Dec 2021",
"name": "Anne-Christine Bay-Jensen",
"expertise": [
"Reviewer Expertise Development and testing of biomarkers in healthy and rheumatology."
],
"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 technical detailed manuscript on a well designed study. It is heavy to read, but informative.\n\nComments:\nWere all biomarkers measurable in all subjects? If not, which value was given for the unmeasurable levels?\n\nTable 5: Does this really provide valuable information, as it is the same as figure 7 (if I understand it correctly).\n\nFigure 8: Is it necessary to show both figure 7 and 8 (correlations of relative vs. absolute change)? or could one of them be cited in the text? One of them seems enough to support the conclusion.\n\nThe reference is just a suggestion to the author of including the reference as part of the background information.‘The reference is just a suggestion to the author of including the reference as part of the background information.\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": "7611",
"date": "11 Jan 2022",
"name": "Annegret Mündermann",
"role": "Author Response",
"response": "Dear Dr. Bay-Jensen, We would like to thank you for your feedback and your comments. We believe that the quality of our manuscript has improved by addressing the comments received. Please find our response to the comments below. Your comments by the reviewers are shown in quotation marks, our responses are shown below each comment in regular font. “Were all biomarkers measurable in all subjects? If not, which value was given for the unmeasurable levels?” Response: All biomarkers were measurable in all subject except ADAMTS-4 in subject 110. As described in the original manuscript, in this subject the values of ADAMTS-4 fluctuated much more than in all other participants and were outside the detection limits, and hence we excluded this subject from the analysis of ADAMTS-4. “Table 5: Does this really provide valuable information, as it is the same as figure 7 (if I understand it correctly).” Response: The reviewer is correct that the Table and Figure contain some overlapping information. We now only report p-values in revised Table 5. Please note that the same point applies to Table 6 and Figure 8, and we have changed Table 6 accordingly. Please also note that the Table header of table 5 contained an error as absolute and not relative changes were correlated. We have corrected this error. “Figure 8: Is it necessary to show both figure 7 and 8 (correlations of relative vs. absolute change)? or could one of them be cited in the text? One of them seems enough to support the conclusion.” Response: We agree that both Figures convey the same message. However, some previous studies report absolute values, and other report relative values. We believe that it is important to show that the results differ slightly whether one or the other is used but that the general pattern is the same. Hence, we think that it is important to show both Figures. “The reference is just a suggestion to the author of including the reference as part of the background information.” Response: Thank you for providing this relevant and interesting reference that was published after our original manuscript was submitted. We now cite this reference in the introduction and discussion section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-490
|
https://f1000research.com/articles/11-26/v1
|
11 Jan 22
|
{
"type": "Research Article",
"title": "Mental illness due to homelessness: a qualitative case study in Melaka, Malaysia",
"authors": [
"Noor Ashikin Mohd Rom",
"Mohamad Lusfi Yaakob",
"Nurbani Md. Hassan",
"Hani Suhaila Ramli",
"Mohamad Lusfi Yaakob",
"Nurbani Md. Hassan",
"Hani Suhaila Ramli"
],
"abstract": "Background: Extreme poverty can result in people barely surviving with poor living standards to the extent of living on the streets, often in fear. With limited access to healthcare services and a clean environment, they are more vulnerable to life adversities. Highly stressful living conditions like these can cause mental illnesses such as depressive disorders, anxiety disorders, psychological distress, and others. Purpose: This research aimed to investigate factors that led to the development of mental illness among homeless people under extreme poverty. Design/methodology/approach: This was a qualitative case study that involved a face-to-face interview with a key informant at the Pertubuhan Kebajikan Villa Harapan Melaka (Villa Harapan). Villa Harapan is a licensed caretaker centre established by the Department of Welfare, Melaka that provides shelter to homeless people with mental illness. Findings: Homeless people suffered from mental disturbances due to loss of jobs, lack of income, broken families, separation from their children, and other vulnerabilities. They are not getting appropriate care and attention for their problem and sickness. Non-supportive family, extreme poverty, and chronic stress were the main factors that led to mental illness among Villa Harapan residents. Research limitations: The study focused on the mental illness of dispossessed people who were brought to Villa Harapan by the Welfare Department. Originality/value: This was an empirical case study on mental illness among homeless people at a care centre known as Villa Harapan.",
"keywords": [
"Mental illness",
"homelessness",
"support",
"poverty"
],
"content": "Introduction\n\nPoverty is related to the lack of food, clothing, shelter, or a general deficiency of necessities for physical wellbeing.1 Poverty is related to income level and rate of school dropouts.2,3 The Malaysian Poverty Line Income (PLI) in the year 2020 ranged from RM908 (USD220) to RM2,208 (USD532) monthly.4 PLI represents the minimum amount of monthly income considered sufficient to accommodate the basic needs of a household.\n\nTraditionally, research on mental illness has been conducted within the psychological field5 in relation to brain functions, the symptoms of its dysfunctionality, and possible pharmacological treatment. Furthermore, evidence has shown that the lack of income can adversely impact mental health6 and predisposes individuals to mental disorders, such as schizophrenia.7 Depression secondary to low quality of life has also been linked to a higher risk of suicidal behaviour.8 In addition, mental diseases also lead to productivity loss as people cannot work due to disability or sickness.9\n\nTo date, there is a lack of research on the association between mental illness and social factors. Therefore, this research attempted to explore possible predisposing factors of mental illness. The Pertubuhan Kebajikan Villa Harapan (Villa Harapan), a licensed centre established by the Department of Welfare in Melaka that provides shelter for homeless people with mental illnesses from different backgrounds. Villa Harapan is the only shelter for mental illness in Malaysia.\n\n\nVilla Harapan background\n\nVilla Harapan was established on 17th May 2010 by the former Chief Minister of Melaka, Mohamad Ali Rustam. It is located approximately 10 km from Melaka City and 140 km from Kuala Lumpur. It is surrounded by shady palm oil trees and green forest, far away from residential and business areas but still accessible by car. Galvanized mesh wire fences and an asphalt road encircle the perimeter of Villa Harapan. It is a small complex with three single-storey buildings connected by covered walkways. The main building in the middle is flanked by two buildings on the left and right, one each for male and female residents respectively. Villa Harapan is staffed by 11 employees, including a nurse. The residents are mainly homeless with mental illness between 22 and 86 years old, with 40% of them being above 50 years old.\n\nThe researcher selected the manager of Villa Harapan as an informant in this study based on her knowledge about homeless persons with mental illness under the care at Villa Harapan.\n\n\nRelated work\n\nHomeless people are more predisposed to mental illness due to higher levels of stress from joblessness and isolation from relatives and peers. Living on the streets can lead to anxiety, misery, fear, insomnia. Homeless persons often fall to drug abuse as a coping mechanism. It was reported that having a safe shelter promoted the recovery of mental illness patients because they can focus on treatment and rehabilitation in the safe environment. According to the National Mental Health Commission, housing availability, homelessness, and mental health are all closely related.10,11 Commonly, people who suffer from mental illness are from poor families and have lower levels of education. Homelessness is closely associated with higher levels of mental distress.12,13 Poor social connection, deprived economic condition, and collapses of close relationships are the main driving factors of homelessness.14\n\n\nMethods\n\nThis research employed a case study method. A case study is useful when there is a need to obtain an in-depth analysis of an issue, event, or phenomenon of interest in a real-life context.15 Purposive sampling was applied in this study. The researcher used a telephone call to contact Villa Harapan and requested for a meeting with their management officers. The purpose for the request was explained and the management gladly welcomed the researcher and a suitable date for an interview was agreed. The researchers prepared an interview guide for the purpose of exploring issues which may brought forward by the participant. The manager agreed and a suitable date was set for an interview. Following that, the researcher attended the meeting at the management office of Villa Harapan. One of the managers was chosen to be interviewed as she had vast experience in handling people with mental illness.\n\nBefore the interview began, the researcher once again introduced herself and explained the purpose of her visit. The participant agreed to be interviewed and signed an informed consent form. There was another officer during the interview. The researcher is a female academician holding a Master’s Degree with more than 12 years’ experience at Multimedia University. The researcher informed the interview would be recorded with an electronic audio recorder. Then the researcher initiated an ice-breaking session to make the participant more at ease during the interview. The participant was able to warm up and the vibrant spirit continued throughout the whole interview. The face-to-face interview provided a lot of freedom for the participant to express what was in her mind.\n\nThe audio recording was listened to multiple times and transcribed verbatim after the interview. Analysis was carried out in stages. First, the audio was transcribed into text. The transcripts were read repeatedly to obtain an overall impression of the interview. This process helped the researchers to familiarise themselves with the data and identify relevant points. The researchers asked common questions such as “What is the participant saying?” or “What happened here?” for selected passages in the text. Data coding was performed manually using paper and pencil by three researchers. Manual coding was acceptable for a small-scale project.16 The coding process was an important part of the data categorisation and analysis. The first cycle of coding was relatively easy in which codes were assigned to each line of the text in the transcript. The initial codes provided an overall understanding of the data. Data validation was performed by providing the interview transcript to the participant to obtain her comment on whether the final themes crafted adequately reflected the phenomena that were being investigated. The result was corroborated by comparing the outcomes from other published papers that explored the same phenomenon.\n\n\nFindings\n\nThe majority of the text was labelled with the general codes. The codes were then refined and rearranged to determine the patterns. Table 1 illustrates the initial codes derived from the transcripts.\n\nThe initial codes were compared and reorganised to obtain distinctive patterns. Similar codes or codes that shared something in common were grouped. The grouped codes formed categories. The most significant categories relevant to this research were selected in the process of determining the emerged themes. The themes were derived from the data which were the outcome of the coding process. The final themes determined included “extreme poverty”, “lack of family support”, and “mental illness” (Table 2).\n\n\n\na) Live on the street.\n\nb) No income.\n\n\n\na) She stayed just outside the McDonald's restaurant.\n\nb) When they ran away from home, away from families without any source of income, they became homeless.\n\n\n\na) Broken family.\n\nb) The unwillingness of family to take care of them.\n\nc) Longing for family love and attention.\n\n\n\na) Most of the Villa Harapan residents came from broken families.\n\nb) Their families refused to take them home.\n\nc) She went to the same spot on the street because her daughter was working in the same area.\n\n\n\na) Importance of medication.\n\nb) Not getting appropriate care and attention for their problem and sickness.\n\n\n\na) Their family must look after them and be alert to the medication routine.\n\nb) Even people with other types of health problems such as cancer or fibroid would not go to a hospital because of reasons such as financial distress and feeling of not being cared for.\n\nSome of the residents in Villa Harapan ran away from home due to family conflicts and feelings of being neglected. They had no place to go and ended up living on the streets. This scenario was highlighted from the following excerpt:\n\n“When they ran away from home, away from families without any source of income, they started to become homeless. There was one girl who hated her stepfather. Hence, she left home. That was how she became homeless and eventually suffered mental illness. One hardship led to another.”\n\nMost of them could not find a job to sustain their daily lives. They were also constantly exposed to various social problems. These stressors increased their vulnerability to high levels of stress and anxiety. Due to the lack of financial means, they failed to obtain prompt medical treatment for their illness, thus prolonging the ailment. Inability to work or generating income is a major part of the problem faced by homeless people that further jeopardises their quality of life. In addition, homeless people also did not have proper access to the water supply to drink and or to clean themselves, not to mention the lack of clothing and food to stave off hunger. As a result, poverty can adversely affect people in many ways, including the deterioration of physical and mental health.\n\nThe poverty level of the homeless is extremely high as shown in previous studies.12,13,18 The lack of monetary resources, basic needs, and capabilities are the main contributing factors to poor mental health among homeless people.17\n\nRegardless of age, both young and old people need family support. Humans are social creatures that cannot live alone. Financial and emotional wellbeing are parts of human needs. People who are neglected or being far away from family members with no financial and emotional support are highly vulnerable to life adversities that may not be visible to others. The participant highlighted this issue by saying:\n\n“Most of the Villa Harapan residents came from a broken family. When they were at home they didn’t receive the much-needed attention and care. They felt neglected and unwanted.”\n\nMost homeless people who suffer mental illness did not receive the necessary support from their family and society.10,17 A complete failure of relationships with people closest to them became the final straw that drove them to homelessness.14 Homeless people are the side-lined groups that are omitted from the communities. They often stay away from others due to various reasons.19,20\n\nPeople who were sent to the Villa Harapan were provided with certain support in the form of food, clothing, medical treatment, and more importantly, the touch of human love, care, and attention from the staff. They also received a safe shelter that they could call home and treated the staff as their family members. A few of them managed to recover from the mental illness and returned as volunteers at Villa Harapan.\n\nThe mental distress of living in poverty may result in the wrong decision-making of leaving one’s home to live on the streets. Homelessness can predispose to a high level of stress. People with chronic stress can recover with proper care and medication with sufficient time and patience. However, poverty often hinders these people from seeking medical treatment. Family members play an essential role in taking care of the wellbeing of those who were less fortunate. The participant voiced the following opinion:\n\n“Their family must look after them and be alert of the medication routine. A few of them showed improvement. They were allowed to go home provided that their family members were willing to provide proper care and attention. Otherwise, their mental illness will recur.”\n\nA few residents with mental illness at Villa Harapan improved with medication and could turn over a new leaf. However, they must be compliant with their medication. Therefore, the task of ensuring medication compliance became the responsibility of the family members.\n\nHomelessness is frequently related to higher levels of stress, anxiety, and desolation.10–13 Unpleasant childhood experiences, behavioural disorders, and unstable emotions are all closely related to subsequent homelessness.21–23\n\n\nConclusion\n\nPoverty stems from mainly a lack of income. People will easily become lost and helpless when faced with poverty, especially if they lack family support or continue to be in prolonged vulnerability. Living under bare necessities on the streets is extremely harmful to emotional wellbeing. All homeless people deserve attention from family, peers, society, organisation, and government. Villa Harapan is the only care centre for homeless people with mental illness in Malaysia. The government should establish more centres like Villa Harapan in other states of Malaysia. Homeless people can recover from mental illness if they are provided with safe shelter, proper care, and medical treatment. Government agencies such as Jabatan Kebajikan Masyarakat (Welfare Department) and other relevant health services must provide the necessary assistance to homeless people at an early stage to prevent the development of mental illness. Family members, especially those with poor socioeconomic backgrounds, should be supported with some monetary or non-monetary benefits to relieve their burden. With these incentives, more will be willing to take care of family members with mental illness.\n\n\nGrant information\n\nA Fundamental Research Grant Scheme (FRGS) FRGS/1/2019/SS06/MMU/03/1 was awarded to the researchers by the Ministry of Higher Education, Malaysia in 2019. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\n\nAuthor contributions\n\nThe first author carried out the research, conceptualised the central research idea, provided the theoretical framework, and wrote the paper. The second author transcribed the interview and revised the article. The fourth author conducted the interviews while the third author reviewed and approved the article submission.\n\n\nData availability\n\nFigshare: Underlying data for ‘Mental illness due to homelessness: a qualitative case study in Melaka, Malaysia’. https://figshare.com/s/9158865f4219efc5c7d6\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthics approval and consent to participate\n\nEthical Approval No.: EA1042021 for Homeless project was obtained from Technology Transfer Office (TTO), Multimedia University. Participant has given written consent to publish.\n\nData set: https://figshare.com/s/9158865f4219efc5c7d6\n\nEthical Approval No.: EA1042021 from Technology Transfer Office (TTO), Multimedia University",
"appendix": "Acknowledgements\n\nWe thank the Chairman of Pertubuhan Kebajikan Villa Harapan Melaka, Malaysia, Mr. Zainal Abidin for allowing us to conduct an interview with their key personnel.\n\n\nReferences\n\nWorld Bank: The Definitions of Poverty.2018.\n\nJamaluddin Z: Kemiskinan dan Keciciran dalam Pendidikan. Jurnal Kebajikan Masyarakat. Jun 2011; 30: 5–17.\n\nKorayem K, Mashour N: Poverty in Secular and Islamic Economics; Conceptualization and Poverty Alleviation Policy, with Reference to Egypt. Topics in Middle Eastern and African Economic. 2014; 16(1). May 2014.\n\nDepartment of Statistics Malaysia: 2020.\n\nSalleh MR: The Burden of Mental Illness: An Emerging Global Disaster. J. Clin. Health Sci. 2018; 3(1): 5–12. Publisher Full Text\n\nMandemakers JJ, Monden CWS: Does the effect of job loss on psychological distress differ by education level?. Work Employ. Soc. 2013; 27(1): 73–93. Publisher Full Text\n\nVolavka J: Violence in Schizophrenia and Bipolar Disorder. Psychiatr. Danub. 2013; 25(1): 24–33. PubMed Abstract\n\nRajkumar RP: Depressive Symptoms during an Acute Schizophrenic Episode: Frequency and Clinical Correlates. Depression Research and Treatment.2015.\n\nOrganisation for Economic Co-operation and Development Directorate for Employment, Labour and Social Affairs (OECD): Sickness, Disability and Work. Keeping On track on Economic Downturn, in High-Level Forum, Stockholm, 14-15 May 2009.2011.\n\nMacnaughton E, Nelson G, Piat M, et al.: Conception of the Mental Health Commission of Canada’s At Home/Chez Soi Project Cross-Site Report Mental Health Commission of Canada National Qualitative Research Team for the At Home/Chez Soi Project.2010.\n\nAubry Y, Nelson G, Tsemberis S: Housing First for People With Severe Mental Illness Who Are Homeless: A Review of the Research and Findings From the At Home–Chez soi Demonstration Project. Can. J. Psychiatry. 2015; 60(11): 467–474. Publisher Full Text\n\nCastellow JKB, Townley G: Previous homelessness as a risk factor for recovery from serious mental illness. Community Ment. Health J. 2015; 51: 674–684. PubMed Abstract | Publisher Full Text\n\nAyano G, Assefa D, Haile K, et al.: Mental, neurologic, and substance use (MNS) disorders among street homeless people in Ethiopia. Ann. General Psychiatry. 2017; 16: 40. PubMed Abstract | Publisher Full Text\n\nMabhala MA, Yohannes A, Griffith M: Social conditions of becoming homelessness: Qualitative analysis of life stories of homeless peoples. Int. J. Equity Health. 2017; 16(150): 1–16. Publisher Full Text\n\nCresswell JW: Qualitative Inquiry and Research Design: Choosing Among Five Approaches. Thousand Oaks, CA: Sage; 2013.\n\nSaldana: The Coding Manual for Qualitative Researchers. London: Sage; 2013.\n\nSylvestre J, Notten G, Kerman N, et al.: Poverty and Serious Mental Illness: Toward Action on a Seemingly Intractable Problem. Community Psychology. 2018; 61(1-2): 153–165. Publisher Full Text\n\nTimmer DA, Stanley Eitzen D, Talley KD: Paths to Homelessness, Extreme Poverty and the Urban Housing Crisis. Routlege: Taylor & Francis; 2019.\n\nOmar N, Jasni MA: Preface. Abd Wahab H, Chowdhury HS, Abu Bakar Ah SH, et al., editors. Challenges of the Homeless People During the COVID-19 Pandemic: Situation in Kuala Lumpur, Malaysia in Handbook of Research on the Impact of COVID-19 on Marginalized Populations and Support for the Future. IGI Global; 2021; 153–166.\n\nDrani S, Azman A, Jamir Singh PS, et al.: Do Homeless People Giving Up Hope? A Qualitative Study in Penang, Malaysia, Asian Social Work Journal. 2021; 6(5): 1–10.\n\nPatterson ML, Moniruzzaman A, Somers JM: History of foster care among homeless adults with mental illness in Vancouver, British Columbia: precursor to trajectories of risk. BMC Psychiatry. 2015; 15(1): 32. Publisher Full Text\n\nRoos LE, Distasio J, Bolton S-L, et al.: A history in-care predicts unique characteristics in a homeless population with mental illness. Child Abuse Negl. 2014; 38(10): 1618–1627. PubMed Abstract | Publisher Full Text\n\nHaskett ME, Armstrong MJ, Tinsdale J: Developmental status and social emotional functioning of young children experiencing homelessness. Early Childhood Educ. J. 2016; 44: 119–125. Publisher Full Text"
}
|
[
{
"id": "119417",
"date": "02 Feb 2022",
"name": "Noralina Omar",
"expertise": [
"Reviewer Expertise social work",
"social intervention"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, the work is presented clearly and well explained. The findings may give new information, knowledge, and insight regarding mental illness among homeless people. The conclusion is sound, good, and impactful.\nTo improve the quality of the manuscript, here are my suggestions:\nAdd one more keyword on abstract - life adversities.\n\nExplanation on chronic stress (findings): Some explanations are inappropriate. For this part, just focus on how chronic stress contributes to mental illness, omit the explanation regarding the support (family members) or move it to 'lack of family support' part.\n\nIt would be more proper if 'findings' section end with conclusion sentences to summarize the findings.\n\nIn the title: Melaka change to Malacca\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": []
},
{
"id": "205860",
"date": "25 May 2024",
"name": "Coline van Everdingen",
"expertise": [
"Reviewer Expertise I'm working as an independent researcher with the background of a Medical Doctor. I'm a public health specialist. I obtained an appointment as a PhD candidate at the psychiatry and neuropsychology department of Maastricht University",
"since I interviewed a large (representative) sample of homeless service users in The Netherlands. My peer reviewed publications provide insight in my expertise in the field of health visions",
"health assessments",
"the relations between (mental) health - homelessness - contextual conditions",
"and quantitative and qualitative 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\nReview report First impression: The authors present a qualitative single case study focusing on the association how mental illness and social factors relate. The data was collected in Villa Harapan, the only shelter for mental Illness in Malaysia. The paper considers an important subject. The quality of the English makes the paper easily accessible. More careful reading reveals structural issues and additional opportunities for improving this paper.\nStructural issues: Design: The authors use a single case study for an in-depth analysis of the results. The case consists of (the users of) the only shelter for mental Illness in Malaysia, Villa Harapan. The authors describe how they contacted Villa Harapan, prepared an interview guide, and interviewed one of the managers with “vast experience in handling people with mental illness.” Essential information is missing. The collected data are limited to the single observations/interpretations of one single manager. By contrast, “Nothing about us without us” is one of the golden rules in the consumer/survivor literature. It remains unclear why the management was interviewed instead of the users themselves? Further, it’s unclear why only one manager was interviewed. Conducting a focus group or group interview with the management team would have contributed to the validation of the data.\nIntroduction: The context description stimulates the imagination. The authors need to provide clarity at two points. First, the authors need to elaborate further on the definition/manifestations, the prevalence/estimated figures and (policy) context of homelessness in Malaysia. What about the presence and extent of (factual and hidden manifestations of) homelessness in Malaysia? What about the context of mental health services and hospitals? What about the policy for people at risk of or experiencing homelessness. Are there, besides Villa Harapan, additional ‘regular’ shelters for homeless people without (severe) mental illness? Second, the authors describe the number of staff members. Essential information on the (numbers and changes in the) service user population is missing.\nApproach of health and recovery: In-depth case studies require a thorough summary of relevant literature. The study aims to uncover qualitative data on the social conditions leading into homelessness. The authors cite relevant publications for providing a summary of relevant factors but remain unclear about the approach of health and recovery. Between the lines, the paper breathes the dominance of a biomedical approach. The authors need to discuss relevant papers, for instance of the WHO, more thoroughly.\nMethods: The authors prepared an interview guide, but its focus remains vague. In the end, the results and the source data point out that the manager was interviewed to collect data on the service users. Please add your research questions for making the focus of the data collection transparent. The paper aims to focus on the social conditions leading into homelessness. In fact, the single interview of a manager presents a cross-sectional view of the usual patterns. What does the data reveal about the resilience and the resources of the homeless service users and their networks?\nTitle Homelessness and mental illness are complex problems. Of course, such interdependent problems are attended with interrelated behavioral and contextual factors. Though the title suggests a linear approach, the paper shows that the authors recognize the complexity of the subject. Please choose a title that matches the operationalization in this paper.\nAdditional opportunities for further improvement Composition of service user population Please, add the mean age and sex of the service users.\nThe interactions between service users and communities/society: At the middle of page 5, the authors briefly discuss what happens in the relations of the homeless service users with their families and society. “They often stay away from others due to various reasons.” This is too vague. Please elaborate further on this issue.\nDiscussion section The discussion section is completely missing. Please add a discussion section and discuss the findings in relation to the literature. What learn this study about the Malaysian context? What makes this paper interesting for an international audience? The current citations mainly relate to the situation in high-income countries. What can we learn of this paper on the character and role of relevant social conditions in low- and middle-income countries?\nTo conclude The comments are set up to encourage the authors to improve the paper. I’d like to continue the dialog on this qualitative study by reviewing the next version of 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? 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? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-26
|
https://f1000research.com/articles/11-25/v1
|
11 Jan 22
|
{
"type": "Data Note",
"title": "Dataset: Knowledge and attitude retention following an implicit bias classroom workshop",
"authors": [
"Yuanyuan Zhou",
"Joel Purkiss",
"Malvika Juneja",
"Jocelyn Greely",
"Anitra Beasley",
"Anne Gill",
"Joel Purkiss",
"Malvika Juneja",
"Jocelyn Greely",
"Anitra Beasley",
"Anne Gill"
],
"abstract": "Background: Baylor College of Medicine provides a classroom-based implicit bias workshop to all third-year medical students to increase students’ awareness of their unconscious bias and develop strategies for reducing health care disparities. The workshop meets our immediate goals and objectives. However, we are unsure if the benefit would be long-term or diminish over time. Methods: To examine the concept retention from the implicit bias classroom workshop, we administered a self-developed seven-item seven-point Likert-scale survey to our medical students at pre-, post-, and one-year post-workshop attendance. Results: The data set was comprised of survey results from two cohorts of our third and fourth-year medical students from 2018 to 2020 and included 289 completed records at three measurement points. The data included: Student Identifiers, Sex, Race/Ethnicity, Student Enrollment Type, Cohort, and three repeated measures results for each of the seven items, which were documented in wide format. The data may be of interest to those who wish to examine how factors including elapsed time, race, and sex may associate with attitudes and understandings of implicit bias following related training, and those interested in analytical methods on longitudinal research in general.",
"keywords": [
"implicit bias",
"classroom workshop",
"repeated measures",
"Likert scales survey",
"unconscious bias"
],
"content": "Introduction\n\nBaylor College of Medicine (BCM) has a long history of educating medical students to develop awareness of their potential inherent bias towards specific racial/ethnic groups that might influence their medical decision-making.1–4 Educators and researchers at BCM developed a classroom-based implicit bias workshop, which has been part of the third-year medical student curriculum since 2008.5 The workshop is currently part of a third-year course on social determinants of health and includes administration of the Implicit Association Test6 (IAT), student review of two articles7,8 about implicit bias in medical education, and small-group discussions. The IAT was used to examine students’ inherent predispositions based on certain demographic groups (e.g., race, weight), with the aim of triggering students’ self-awareness and self-reflection of their unconscious bias. The students were told to read the two articles before the session and to discuss them during the small group session. The literature review allowed examination of how such unconscious bias may influence physicians’ clinical decision-making and was followed by active small-group discussion which fostered engagement with management strategies for reducing health care disparities (a schematic overview of the research design can be found in Figure 1).\n\nSuch educational practices have demonstrated an effective immediate influence on students’ awareness and management of implicit bias.4 However, we were uncertain whether this immediate impact following the one-session workshop would be sustained over time. If the educational effects of the IAT workshop diminish over time, a one-time classroom workshop may not be sufficient in preventing health care disparities among certain social groups. Offering more training in this area to our medical students would require additional time and resources in an already compressed curriculum. A better understanding of how the effects of implicit bias training persist following a classroom workshop would enable medical schools to design and develop curricula which maximize training efficiency and students’ future development as physicians.\n\nThe research manuscript generated from this study has been Accepted by Medical Teacher for publication and is in press. However, the data might be valuable for those wishing to pursue additional secondary analyses of related research topics, or a meta-analysis that combines multiple independent scientific studies of similar topics. These data might also be valuable for those interested in using other analytical methods to investigate the same research question or even for new longitudinal research simply focusing on the analytical methods in general, beyond the topic of the implicit bias.\n\n\nMethods\n\nThis data set was collected as part of ongoing curriculum evaluation and improvement process. However, when aggregated together for the purposes of this project, the data comprise a longitudinal observational study that measures students’ attitudinal change over three repeated measures: immediately before participating in the workshop, immediately after participating in the workshop, and one year after participating in the workshop (measurement timing can be found in Figure 1).\n\nThe implicit bias workshop was administered within the required Determinants, Disparities, and Social Health of Populations (D-DASH) course. All third-year students who took the D-DASH course were considered as potential participants in this study. They were informed of the purpose of this study prior to agreeing to complete the survey and learned that information collected through the survey would be used as part of a research protocol. They received the pre-and post-surveys through the web-based course evaluation platform e*Value.\n\nApproximately one year later, we conducted a one-year post-survey of the students during their fourth year as part of their required capstone course, Advanced Physician Experience (APEX). All students in APEX courses were informed again that the survey was part of a research protocol and they were voluntarily agreeing to participate the study.\n\nThe study was based on data collected between 2018 and 2020 from two cohorts of medical students (Class of 2019: n = 168; and Class of 2020: n = 185). Each class of students first received the pre- and post-surveys in their third year (MS3) spring D-DASH course and then completed the same survey the following spring in their fourth year (MS4). Due to merged curricular tracks, there was a small portion of students who did not receive the implicit bias surveys and training in their MS3 spring, but still received the one-year post-workshop-survey in their MS4 spring term. These off-track students did not meet the research criterion and were excluded from the data analysis.\n\nMembers of the BCM research team created the survey for this study in 2008, when the implicit bias workshop was offered to students and it has been revised and refined several times based on piloted data and students’ feedback. The final version included seven questions evaluating students’ thoughts on questions regarding a physician’s or individual’s perceptions and management of unconscious bias. The survey was in a Likert-style format, with seven options ranging from strongly disagree (1) to strongly agree (7) (the survey can be found in the extended data9).\n\nSurveys were distributed through the course evaluation platform e*Value and were active for two weeks to allow students to complete the surveys. The response rates ranged from 92.2% to 100.0% (see Table 1 for complete response rates). Survey data were exported as Excel data files and were saved in a secure/encrypted web portal within the BCM Medicine network. The original data were identifiable, but we deidentified data for subsequent analysis.\n\na Number of students completing the survey.\n\nb Number of students receiving the survey.\n\nThe data file included 26 variables: Student Identifier, Gender, Race/Ethnicity, Student Enrollment Type, Cohort, and 21 variables for the survey results. Student Identifier is a unique number for each student. We used randomly generated 10-digit numbers to replace the original school identification numbers to promote confidentiality of respondent data. Gender was self-defined by students. We allowed students to identify a gender other than male or female with an ‘other’ option and space to write their own answer, but all students identified themselves as either male or female. Students also selected their race/ethnicity. We merged ethnicities into more general and commonly used categories and were left with four options: White, Black or African American, Hispanic, Asian, other Asian, or ‘prefer not to answer’. Student Enrollment Type was a dichotomous variable (“0” or “1”) used to differentiate those who had regular curriculum scheduling for the period under study (“0”) and those who had an irregular curriculum schedule (“1”). There were 17 students in the latter category who completed the one-year post-survey two years after the workshop. These 17 students did not meet the criterion for inclusion in the primary analysis. However, this small sub-sample provided a less robust but still intriguing opportunity to examine for retention of the implicit bias training following an even longer elapsed period after the classroom workshop had been conducted.\n\nCohort included the 2019 Cohort who took the pre- and post-survey in 2018, and the one-year post-survey in 2019; and Cohort 2020 who took the pre- and post-survey in 2019, and the one-year post-survey in 2020. The survey results have 21 variables because the survey had seven Likert-style items, and each was measured three times. The Likert-style items were coded in numerical format, ranging from 1 to 7 (1 for Strongly Disagree, 7 for Strongly Agree).\n\nWe merged the three longitudinal surveys’ results into one file using the unique identifiers assigned to each student. The dataset can be found in underlying data.9 We deleted 94 records that did not meet the research criterion: 37 records for those without the pre-survey, three records for those without the post-survey, and 54 records for those without the one-year post-survey. Those without the pre-or one-year post-survey were likely to have irregular curriculum scheduling due to a leave of absence or enrollment in an extended-time and off-cycle dual degree program. Those without the post-survey likely failed to submit responses to the post-survey.\n\nA total of 289 records were available with completed measures at three measurement points, of which 272 students were from the regular curriculum tracks (130 from the Class of 2019, and 142 from the Class of 2020), with the remaining 17 having irregular curriculum scheduling (see Table 2). Resulting data were then merged with race/ethnicity, and gender data self-identified by students which was collected previously during the medical school admissions process. Students were aware that the study may report demographics to describe the sample composition.\n\n* These 17 students on irregular curriculum schedules actually completed the “One-Year Post” survey two years after the workshop.\n\n\nData validation\n\nThe data set has been proofread for human errors. A frequency summary table (Table 3) was created using the Pivot function in Microsoft Excel. Measurement results were negatively skewed to more positive options but following application of sampling criteria. There were no missing data for any of the three repeated measures. We evaluated the survey quality using this dataset. Cronbach’s alpha measures the internal consistency of survey items, and ranged from 0.86 to 0.87 between the pre-, post-, and one-year post surveys. The seven items had moderate to high inter-item correlations and had consistent patterns across the pre-, post-, and one-year post surveys. The first factor extracted by Exploratory Factor Analysis explains more than half of the variances, which provided primary evidence of a unidimensional structure of the survey. The results provided some evidence that the survey was still solid and reliable. More detailed results for survey quality can be found in Table 4.\n\n\nEthics statement\n\nThis study and the publication of the data set was approved by The Institutional Review Board for Human Subject Research at BCM (protocol number: H-45073). Written documentation of consent was waived for this study by the review board due to its low-risk nature. The participants were informed of the purpose of the survey while they took the D-DASH and APEX course and that taking the survey was optional, and non-participation would not impact their course grade. They were informed that, by taking the survey, they were voluntarily agreeing to participate in the study. Students were aware that all survey data would be kept confidential, and data would be deidentified for analysis and reporting.\n\n\nData availability\n\nDANS: Implicit bias classroom workshop data. https://doi.org/10.17026/dans-zrv-mxsm.9\n\nThis project contains the following underlying data:\n\n- DataFileImplicitBias.xlsx (dataset and code book for the variables)\n\nThis project contains the following extended data\n\n- Implicit bias survey.pdf (copy of survey).\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\nGill A, Thompson B, Teal C, et al.: Best Intentions: Using the Implicit Associations Test to Promote Reflection About Personal Bias. MedEdPORTAL. 2010; 6(1). Publisher Full Text\n\nHernandez RA, Haidet P, Gill AC, et al.: Fostering students' reflection about bias in healthcare: Cognitive dissonance and the role of personal and normative standards. Med. Teach. 2013; 35(4): e1082–e1089. PubMed Abstract | Publisher Full Text\n\nTeal CR, Gill AC, Green AR, et al.: Helping medical learners recognise and manage unconscious bias toward certain patient groups. Med. Educ. 2012; 46(1): 80–88. PubMed Abstract | Publisher Full Text\n\nTeal CR, Shada RE, Gill AC, et al.: When best intentions aren't enough: helping medical students develop strategies for managing bias about patients. J. Gen. Intern. Med. 2010; 25(S2): 115–118. Publisher Full Text\n\nGill A, Thompson B, Teal C, et al.: Best Intentions: Using the Implicit Associations Test to Promote Reflection About Personal Bias. MedEdPORTAL. 2010. Publisher Full Text\n\nGreenwald AG, McGhee DE, Schwartz JLK: Measuring Individual Differences in Implicit Cognition: The Implicit Association Test. J. Pers. Soc. Psychol. 1998; 74(6): 1464–1480. PubMed Abstract | Publisher Full Text\n\nGreen AR, Carney DR, Pallin DJ, et al.: Implicit Bias among Physicians and its Prediction of Thrombolysis Decisions for Black and White Patients. J. Gen. Intern. Med. 2007; 22(9): 1231–1238. PubMed Abstract | Publisher Full Text\n\nCapers Q, Clinchot D, McDougle L, et al.: Implicit Racial Bias in Medical School Admissions. Acad. Med. 2017; 92(3): 365–369. PubMed Abstract | Publisher Full Text\n\nZhou Y, Purkiss J, Juneja M, et al.: Implicit Bias Classroom Workshop Data. DANS. 2020. Publisher Full Text"
}
|
[
{
"id": "119372",
"date": "04 Feb 2022",
"name": "Xuejun Ji",
"expertise": [
"Reviewer Expertise Psychometrics",
"OSCE examine",
"validity and validation"
],
"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 rationale for the dataset building is fully articulated. The users can access the dataset directly and replicate the results easily. No missing data were found. The codebook is available for users, which allows users to conduct data wrangling and further analysis. Overall, the submitted dataset is a good source for any further studies and replication studies.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "7777",
"date": "04 Feb 2022",
"name": "Yuanyuan Zhou",
"role": "Author Response",
"response": "Thank you for your time to review this paper and provide feedback."
}
]
},
{
"id": "122372",
"date": "24 Feb 2022",
"name": "Ling Ning",
"expertise": [
"Reviewer Expertise My research focuses on multilevel/longitudinal modeling of data with complex structures",
"propensity score analysis",
"and value-added assessment."
],
"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 the manuscript Dataset: Knowledge and attitude retention following an implicit bias classroom workshop for F1000Research. The article was very well written with clear and precise language. The authors did a very good job in articulating the purposes of making the data available for public access. The authors also illustrate very clearly the study design, study population, data collection, aggregation, and validation process.\nMinor points: Page 4 (of the pdf version of the article): about ethnicities: “ …were left with four options…”, not very clear. Not exactly four options.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "123367",
"date": "11 Mar 2022",
"name": "Courtney West",
"expertise": [
"Reviewer Expertise My research interests include",
"but are not limited to",
"learning and study strategies",
"instructional techniques",
"program evaluation",
"professional development",
"and team based collaborative care."
],
"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 rationale for creating the dataset is clearly described. The purpose was to “examine concept retention” from an implicit bias classroom workshop using a seven-item seven-point Likert-scale survey. “The data set was comprised of survey results from two cohorts of third and fourth-year medical students from 2018 to 2020 and included 289 completed records at three measurement points.”\nThe manuscript is well written, and the description of the protocols are appropriate and sound. The results are clearly presented in the text and in the attached tables. They are consistent with the methods used.\n\nThe authors provide sufficient details of how they examined concept retention which would allow replication by others. The data collection methods have been outlined effectively and the data validation process is clearly described so that another researcher could replicate and extend the study. This data note highlights a robust approach that may be adopted and utilized to examine knowledge and attitude retention over time.\nThe datasets are presented in a useable and accessible format. For example, the authors provided a data dictionary/code book on the second tab of the excel data file. In addition, a pdf document including the implicit bias workshop survey was also included as extended data.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-25
|
https://f1000research.com/articles/10-1146/v1
|
11 Nov 21
|
{
"type": "Case Report",
"title": "Case Report: Silicosis and IgA nephropathy, an exceptional association",
"authors": [
"Ikram Mami",
"Jihen Hsinet",
"Syrine Tlili",
"Hela Jebali",
"Ilhem Ben Othmani",
"Saloua Ismail",
"Nihel Khouja",
"Krid Madiha",
"Lamia Rais",
"Aida Benzarti",
"Ben Jemaa Abdelmajid",
"Lilia Ben Fatma",
"Karim Zouaghi",
"Jihen Hsinet",
"Syrine Tlili",
"Hela Jebali",
"Ilhem Ben Othmani",
"Saloua Ismail",
"Nihel Khouja",
"Krid Madiha",
"Lamia Rais",
"Aida Benzarti",
"Ben Jemaa Abdelmajid",
"Lilia Ben Fatma",
"Karim Zouaghi"
],
"abstract": "A 57-year-old male who had been working in masonry for 33 years was hospitalized for renal function decline associated with exertional dyspnea. He presented with hypertension and limb edema. Urinalysis revealed an active urine sediment with glomerular proteinuria at 1.5 g/24h and the renal biopsy identified mesangial IgA Nephropathy. Chest tomography scans showed signs of silicosis. The patient received Angiotensin-Converting Enzyme Inhibitors with stable renal function. To our knowledge, the association of silicosis-IgA nephropathy has rarely been reported in the literature. This case highlights the effect of chronic exposure to silica dust and its association with both silica and renal disease.",
"keywords": [
"IgA nephropathy",
"silica nephropathy",
"silicosis",
"work environment"
],
"content": "Introduction\n\nOccupational exposure to crystalline silica dust particles may lead to silicosis, which is the most common pneumoconiosis. Silica crystalline is known to be a trigger of autoimmune and chronic kidney diseases.1 The most common silica nephropathies described to be related to silicosis are crescentic glomerulonephritis, proliferative glomerulonephritis and chronic interstitial nephritis.1 IgA nephropathy (IgA N) is known to be the most frequent glomerulonephritis. However, silicosis-IgA N is a rare association and very few cases have been reported in the literature.2–6 The underlying pathophysiology remains to be elucidated.\n\nHereby, we report the case of a mason with a coexistent silicosis and IgA nephropathy in order to better understand such association.\n\n\nCase presentation\n\nA 57-year-old Caucasian man was admitted to our department of nephrology for unexplained renal failure (serum creatinine 207 μmol/l, eGFR 26 ml/min) that was discovered during routine exams to follow-up his pernicious anemia, including creatinine, NFS and haemoglobin. The pernicious anemia was diagnosed two years ago and treated by intramuscular injections of vitamin B12.\n\nThe patient had a seven pack-year tobacco smoking history that he stopped 5 years ago.\n\nThe professional anamneses revealed that the patient worked as a mason for 33 years in several constructions and public work companies. He was responsible of supervising concreting, masonry, foundations, walls and floors covering as well as painting and finishing. During his professional career, he was exposed to crystalline silica without wearing respiratory protective equipment.\n\nAt admission, physical examination revealed a blood pressure of 150/90 mmHg and edema in lower limbs. Urinalysis showed an active urinary sediment with significant proteinuria (2+) and microscopic hematuria (3+). We also noticed bilateral clubbing. The patient was also eupneic. Chest auscultation showed diffuse bilateral crackles.\n\nBiological investigations revealed a renal failure with a creatinine level at 207 μmol/l (normal range >60 μmol/l), and positive proteinuria at 1.5 g/24 hours (normal range <0.5 g/24 hours), as well as a macrocytic anemia with a hemoglobin level at 11g/dl (anemia shown by level <13g/dl) and an elevated C reactive protein level at 67 mg/l (normal range <5 mg/l).\n\nP anti-neutrophil cytoplamic (p ANCA), c anti-neutrophil cytoplasmic (c ANCA) antibodies and antinuclear antibodies (AAN) were negative. Serum complement level was normal. CT guided percutaneous renal biopsy as performed using automatic spring loaded needle of 16 gauge under local anesthesia. Thirteen glomeruli were included in the specimen. Five of them were ischemic and sclerosed. The rest of the glomeruli showed focal and segmental mesangial hypercellularity without crescents. There were flocculo-capsular synechiae associated with severe tubular atrophy and interstitial fibrosis. Immunofluorescence revealed granular staining of IgA and C3 in the mesangium. The final pathological diagnosis was IgA nephropathy (Figure 1).\n\nA,B: Light microscopic, hematoxylin and eosin- stained (×200), segmental mesangial hypercellularity. C: Light microscopic, Periodic Acid Schiff (× 200), flocculo-capsular synechiae. D: Immunofluorescence microscopy (×200), Mesangial IgA deposits.\n\nChest tomography was performed and it revealed fibrosing diffuse interstitial lung disease consisting of bilateral septal thickening, ground-glass opacities and a honeycomb pattern. These aspects predominated at the two bases and on the periphery (Figure 2).\n\nBecause of occupational history of chronic crystalline silica exposure, characteristic radiologic findings and clinical signs, the diagnosis of silicosis was given.\n\nThe patient was put on Angiotensin-Converting Enzyme Inhibitors (Ramipril 5 mg/day) because of its antihypertensive and protein-lowering effects and was referred to the pneumology department to complete the respiratory functional exploration and to treat the silicosis. Renal function was stable after three months of follow-up.\n\nFrom a medico-legal point of view, silicosis is considered as a compensable occupational disease, according to the Tunisian list table of occupational diseases.7\n\n\nDiscussion\n\nOccupational silica exposure causes not only lung damages, but also involves many other organs.8 In fact, it was recently noticed that silica exposure is more frequently associated to autoimmune diseases and systemic manifestations such as scleroderma, systemic lupus erythematosus, rheumatoid arthritis or ANCA-associated vasculitis than the general population.8 Little is known about mechanisms, but it has been reported that silica dust triggers autoimmune phenomena.2\n\nMoreover, several authors have reported the association of silicosis with kidney lesions as an occupational disease.9 According to Ghahramani, exposure to silica dust can be associated with tubulointerstitial or glomerulonephritis involvement, which often leads to an important risk of end-stage renal disease.1 The most common silica nephropathy described in the literature were crescentic glomerulonephritis, proliferative glomerulonephritis and chronic interstitial nephritis.3 IgA nephropathy had been rarely reported even though it is the most common type of glomerulonephritis worldwide.10 Only a few similar cases were described in the literature.2–6 A summary of all cases reported has been presented in Table 1.\n\nThe underlying mechanism connecting the two entities is probably that silica behaves as an adjuvant to enhance immunologic and inflammatory process.11 According to the medical history of the association of lung and kidney disease, Endo et al had reported that not only upper tract, but also the lung or lower respiratory tract is a mucosal site protected by IgA.12 Thus, persistent lung inflammation may stimulate IgA mediated immune mechanisms or activate antibody (IgA) dependent monocytes, which leads to IgA mediated immune abnormalities and mesangial deposition of IgA.12 This process mimics the immunopathologic features of IgA nephropathy and may confirm that this glomerulonephritis may occur secondary to silicosis. Beshir et al revealed serum IgA mean level was significantly higher in the silicosis group compared to the non-silicosis group (315.1 ± 165.3 vs. 154.7 ± 105.1 mg/dl, respectively).13\n\nMore interestingly, a recent study may explain the putative link between silicosis and IgA N, which is a NOD-like receptor, pyrin domain-containing 3 (NLRP3). In fact, NLRP3 are the key in the inflammatory process caused by silica: they are involved, in association with alveolar macrophages, in binding and eliminating crystalline silica particles, and thus leading to pulmonary fibrosis in recent studies.3,14\n\nThe real mechanism and pathophysiology are still not fully elucidated and needs more study to further understand how silica leads to autoimmunity and glomerulonephritis. In our case, simultaneous kidney and pulmonary disease could suggest the hypothesis that Ig A nephropathy might be associated with silica exposure.\n\nIn addition, data about silicosis-IgA N treatment is poor and inconclusive, because there are no clinical trials or controlled studies, but only sporadic cases have been reported. According to Ghahramani, there is no specific treatment.1 However, vasculitis and immune-mediated disease required steroids and cytotoxic agents in addition to reducing exposure to silica crystalline dust.8\n\nIn our case, steroids or immunosuppressant agents were not required because of the absence of active lesions on renal biopsy. Thus, only antihypertensive treatment with a nephroprotective effect was initiated in association with a withdrawal from the occupational exposure. Moreover, chronic lesions, such as tubular atrophy and interstitial fibrosis might explain the degree of renal insufficiency and the uselessness of immunosuppressive agents.\n\nMoreover, there is no evident data regarding the course of the association of silicosis and IgA nephropathy. Some authors reported that occupational exposure to silica is associated with an elevated risk of end stage renal disease and thus with high mortality,1 while others had reported that renal disease or progression is associated with a worsening lung involvement.11\n\n\nConclusion\n\nSilicosis-IgA N is a very rarely reported association in the literature. It seems to be far more than an incidental association. The pathogenesis is still not fully understood, and the paucity of information makes a significant barrier to confirm such a link. Nevertheless, according to many authors, the main underlying mechanism is a triggering of autoimmunity with a mal-adaptive immune response. In addition, it is necessary to be particularly vigilant with these rare associations and to think systematically about environmental and occupational exposure.\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 his clinical details and clinical images was obtained from the patient.",
"appendix": "References\n\nGhahramani N: Silica nephropathy. Int J Occup Environ Med. 2010 Jul; 1(3): 108–115. PubMed Abstract\n\nBonnin A, Mousson C, Justrabo E, et al.: Silicosis associated with crescentic IgA mesangial nephropathy. Nephron. 1987; 47(3): 229–230. PubMed Abstract | Publisher Full Text\n\nChen FF, Tang HY, Yu F, et al.: Renal involvement in a silicosis patient - case report and literature review. Ren. Fail. 2019 Nov; 41(1): 1045–1053. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhan AR, Al-Homrany M: IgA nephropathy accompanied by silica-deposited interstitial hephritis. Ann. Saudi Med. 1999 Jan-Feb; 19(1): 45–47. PubMed Abstract | Publisher Full Text\n\nFujii Y, Arimura Y, Waku M, et al.: A case of IgA nephropathy associated with silicosis. Nihon Jinzo Gakkai Shi. 2001 Oct; 43(7): 613–618. Japanese. PubMed Abstract\n\nRiccò M, Thai E, Cella S: Silicosis and renal disease: insights from a case of IgA nephropathy. Ind. Health. 2016; 54(1): 74–78. Epub 2015 Sep 30.PubMed Abstract | Publisher Full Text | Free Full Text\n\nhttp\n\nGómez-Puerta JA, Gedmintas L, Costenbader KH: The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis. Autoimmun. Rev. 2013 Oct; 12(12): 1129–1135. Epub 2013 Jun 29.PubMed Abstract | Publisher Full Text | Free Full Text\n\nGluhovschi G, Velciov S, Petrica L, et al.: Aspects of renal-pulmonary pathogenic replationships in chronic kidney disease and chronic pulmonary diseases--a less-known connection. Rom. J. Intern. Med. 2014 Apr-Jun; 52(2): 68–77. PubMed Abstract\n\nRao N, Bendall A, Lanteri M: ANCA vasculitis and IgA nephropathy linked to silica exposure. Occup. Med. (Lond.). 2020 Sep 9; 70(6): 445–448. PubMed Abstract | Publisher Full Text\n\nD'Amico G: Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin. Nephrol. 2004 May; 24(3): 179–196. PubMed Abstract | Publisher Full Text\n\nEndo Y, Hara M: Glomerular IgA deposition in pulmonary diseases. Kidney Int. 1986; 29: 557–562. PubMed Abstract | Publisher Full Text\n\nBeshir S, Shaheen WA, Elserougy S, et al.: Serum autoantibodies in silicosis and non-silicosis cement workers. Am. J. Ind. Med. 2015 Feb; 58(2): 238–44. Epub 2015 Jan 6.PubMed Abstract | Publisher Full Text\n\nPeng W, Pei GQ, Tang Y, et al.: IgA1 deposition may induce NLRP3 expression and macrophage transdifferentiation of podocyte in IgA nephropathy. J. Transl. Med. 2019 Dec 3; 17(1): 406. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "100173",
"date": "06 Dec 2021",
"name": "Imed Helal",
"expertise": [
"Reviewer Expertise clinical nephrology",
"dialysis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article presents an exceptional association of silicosis and IgA nephropathy excellent for discussion and teaching. Exposure to silica has been associated with tubulointerstitial disease, immune-mediated multisystem disease, chronic kidney disease and end-stage kidney disease. A rare association with glomerunephritis has been reported.\nI read this case report with interest and have a few comments and suggestions:\nThere are several formatting and grammatical errors throughout the manuscript. Please correct.\n\nWith the new published nomenclature in nephrology, please remove renal and write kidney instead.\n\nWhat is meant by the abbreviation NFS?\n\nThe relationship between SILICOSIS and IgA nephropathy is not confirmed. Please provide more evidence.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "7619",
"date": "23 Dec 2021",
"name": "Ikram Mami",
"role": "Author Response",
"response": "There are several formatting and grammatical errors throughout the manuscript. Please correct. Grammatical errors were corrected in the new version. With the new published nomenclature in nephrology, please remove renal and write kidney instead. The term “Renal” is replaced with the term “Kidney”. What is meant by the abbreviation NFS? NFS was translated to English in the new version. The relationship between SILICOSIS and IgA nephropathy is not confirmed. Please provide more evidence. In our case, the diagnosis of silicosis was given by exposure to silica and the results of chest tomography. In fact, the diagnosis of silicosis needs occupational exposure and radiological features, with exclusion of other competing diagnoses. Simultaneous kidney and pulmonary disease could lead to the hypothesis that IgA nephropathy might be associated with silica exposure. In fact, IgA nephropathy seems frequent in patients with various pulmonary diseases, suggesting that an inflammatory process of the lungs may lead to IgA-mediated immune. In our case, the patient had also high C reactive protein level at 67 mg/l which suggests an inflammatory status. Author of this article"
}
]
},
{
"id": "100170",
"date": "09 Dec 2021",
"name": "Gisella Vischini",
"expertise": [
"Reviewer Expertise Renal pathology",
"glomerulonephritis"
],
"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 describe a rare association between silicosis and IgA nephropathy. Based on previous studies already published in the literature, they summarise possible explanations in which hyperstimulation of low respiratory tract mucosa, aberrant IgA production and macrophages activation seem to play a crucial role.\nThe paper is grammatically well written; however, I think it is not enough from a scientific point of view.\nI have expanded upon on my views below:\nIs the background of the case’s history and progression described in sufficient detail? Yes, the clinical history is well reported\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\nNo, they are not. Previous published studies have done more tests on kidney biopsy in order to define the correct diagnosis and its pathogenesis (silica test on kidney biopsy, macrophage activation). Patient’s follow up is three months: KDIGO suggest six months therapy before considering other therapies. I think the observation is too short.\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis, or treatment?\nNo, it is not. The Authors put together findings already published without adding any new elements useful for future understanding of disease processes, diagnosis, or treatment.\nIs the case presented with sufficient detail to be useful for other practitioners?\nYes, it is. The Author report a good practice management.\nI have expressed my negative impression and therefore I did not approve the paper because, in my opinion, a description of a good clinical management not always is associated with a solid scientific process: the paper lacks about specific tests and or pathological findings that we need to have if we want to correlate two otherwise ordinary diagnosis among them. In that case is just a good description of a typical day work where clinicians look for support on papers already published on their clinical hypothesis.\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? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "7624",
"date": "13 Jan 2022",
"name": "Ikram Mami",
"role": "Author Response",
"response": "I want to thank you for agreeing to judge our work. In fact, the association of Ig A nephropathy and silicosis is exceptional and only a few reports were described in the literature. So, further investigations are needed to confirm such a hypothesis, but we think that our data should prompt clinicians to report similar cases to better understand the mechanisms underlying silica nephropathy."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1146
|
https://f1000research.com/articles/10-927/v1
|
15 Sep 21
|
{
"type": "Research Article",
"title": "Enhancing innovative delivery in schools using design thinking",
"authors": [
"Sharmini Gopinathan",
"Anisha Haveena Kaur",
"Kanesaraj Ramasamy",
"Murali Raman",
"Anisha Haveena Kaur",
"Kanesaraj Ramasamy",
"Murali Raman"
],
"abstract": "The pandemic has created challenges in all sectors of the economy and education. Traditional teaching approaches seem futile in the new context, thus the need to constantly reinvent the delivery to meet the fast-paced changes in the education domain. Hence, Design Thinking (DT) is an alternative approach that might be useful in the given context. DT is known to be a human-centric approach to innovative problem-solving processes. DT could be employed in the delivery process to develop twenty-first-century skills and enhance creativity and innovation, in an attempt to identify alternative solutions. The study explores the role of design thinking (DT) mindset in innovative delivery among teachers. It enhances and facilitates innovative content delivery by leveraging creativity. The study targeted 131 teachers from primary and secondary schools in Malaysia. Data was collected through an online survey and was analyzed using SmartPLS to establish relationships between DT and Innovative Delivery in schools. The data was further analyzed to seek co-relations between the DT steps and the successful transformation of content delivery by teachers. The study established a framework for the application of design thinking for teachers as the primary support in developing activities for their students. The outcome of this study will help fill the gap towards creating an interesting method of delivery in schools and constantly innovating the method to suit the evolving generation. It provides an in-depth reason as to why students are not interested in the teacher's lessons which, in turn, affects their performance. This insight is crucial for the Ministry of Education and policymakers to enhance teachers’ ability to innovatively deliver content to students.",
"keywords": [
"Design thinking",
"innovative teaching",
"21st-century teaching",
"Malaysian schools",
"innovative delivery"
],
"content": "Introduction\n\nWe are living in unprecedented times. The COVID-19 pandemic coupled with the continuous onslaught of digital technologies has acerbated the level of volatility, uncertainty, complexity, and ambiguity (VUCA), across various sectors. The education sector is not spared and remains a target for greater industrial shifts and repositioning in the context of remaining relevant. To this end, even schools are subject to changes—failure to innovate and offer the state of curriculum and pedagogy puts extreme pressure on students in their quest to become employable at later parts of life. As such, to ensure the education systems keep abreast with changes, strategic and practical shifts in the delivery of educational content is crucial. Failure to do so could result in longer term socioeconomic consequences.\n\nIn this paper, we posit that innovative delivery of educational content is required to ensure students can truly benefit from the learning outcomes set out in schools. Therefore, we propose precursors such as having empathy, rejuvenated thinking process, curriculum enhancement and gamification of lessons that can lead to innovative delivery of lessons. This includes examining the role of design thinking (DT) in generating innovative delivery of educational content.\n\nThere are various definitions of design thinking. According to Oxford Languages1, the word ‘design’, a noun, refers to “a plan or drawing produced to show the look and function or workings of a building, garment, or other objects before it is made”. This definition implies that ‘design’ relates to any form of idea that is put forth either in the form of sketch, model, or better still as a full-blown prototype before the final product or model is developed. The second word, ‘thinking’, a noun, refers to “the process of considering or reasoning about something,” according to Oxford Languages2. The keywords based on this definition are reasoning and process. DT therefore can be defined as a systematic or a structured approach to developing something, initially as a model or prototype, before a final version is built. We need to understand nevertheless that when people build or develop something, it is often done to solve a real-world problem. As such, DT is often defined as a systematic and structured approach to solving a problem based on design.\n\nThe inherent ideas beneath DT are not new. Nevertheless, DT presents an organised way of including innovative thinking and creativity in organisations. To be able to derive the inspirational values of DT, highly specific tools and techniques are used that are usually presented in a simplified manner. DT is able to solve problems using a user-centric collaborative method3. Stanford University’s design school (dSchool) established a five-step DT process4, which is summarised in Table 1.\n\nDT when institutionalised as an inherent culture in schools, could lead to innovative teaching and learning processes. Specifically, DT has the potential to cultivate empathy, lead to a growth mindset (new thinking processes), and lead to curriculum enhancement in the form of gamified learning.\n\nEmpathy as a core of every DT project, one outcome of successful DT applications is the ability to encourage a culture that gives everybody a chance to express themselves freely. Empathy in the classroom context refers to the teacher-student interaction. Empathy shows the connection of what a teacher thinks or knows about their students and what they do to provide the necessary response to the students’ needs5. This is also needed as teachers are the ones who arrange learning experiences for their students. Teachers are able to do so by providing feedback to their students. According to Mueller and Dweck6, students who are praised and given feedback based on their efforts (instead of intelligence) are more likely to show an interest in mastery and tend to seek challenges when attempting to achieve their learning goals. These students can think out of the box as they are under the impression that their performances can be improved7.\n\nInnovative and creative thinking is the product of DT’s ideation. The thinking process closely relates to the Growth Mindset Theory by Dweck8. Students with a growing mindset tend to learn through persistence, failure, and different strategies. Additionally, students are able to overcome challenges given to them by practicing and using setbacks as a form of motivation. Implementation of innovative teaching strategies such as collaborative learning, using real-life problems to address issues, and experimentation also contribute to the thinking process9. According to the Cambridge Learning Attributes Guide10, the thinking process is a powerful tool which not only requires knowledge and understanding of a subject matter but also the students’ willingness to question it. By ensuring that students are provided with materials that enable them to challenge the subject matter they will be able to express their own understanding and opinions on it.\n\nPrototyping in DT leads to a new form of learning, which in this context refers to gamification. Gamifying lessons enables teachers to establish a casual learning environment whereby students are able to challenge themselves via fun online games11. According to Hakak et al.12, students are given tasks or “missions” with varying levels of difficulty and they are required to complete them within a short time frame. They are also given the chance to repeat the “mission” if they fail to achieve the goal. This allows students to analyse and correct the mistakes made, which in turn encourages them to build a positive attitude towards learning13. Eleftheria et al.14 believe that the use of gamification provides students with a comprehensive understanding of the subject being taught and it increases their engagement and enjoyment in the learning process.\n\nCurriculum enhancement is the product of testing from DT. The materials provided in an enhanced curriculum should allow students to deeply reflect the topic at hand and provide them with the opportunities to make connections between other subjects and topics as well10. Additionally, the curriculum should look beyond testing. Assessments in the form of evaluating students’ points of view and their observations are important as this shows the process of their progression15. Teachers are also advised to consider implementing more group work and interactive lessons which builds on what students already know. From there, students are able to apply existing knowledge and add value to new knowledge.\n\nAs such, this paper aims to answer the following research questions:\n\n1. Is there a relationship between DT and innovative delivery of teaching content in schools, specifically using the stage called empathy?\n\n2. In addition to DT and empathy, what role does new thinking process, curriculum enhancement and gamification of lessons play towards similar aspirations?\n\nHence, the fulcrum of the study’s objectives is:\n\n1. To determine if DT in the form of empathy leads to innovative delivery of curriculum\n\n2. To examine if DT can lead to new forms of thinking processes and thus lead to innovative delivery of curriculum\n\n3. To assess whether DT does lead to innovative delivery of curriculum, by promoting curriculum enhancement and gamified approach to teaching and learning.\n\n\nMethods\n\nThis research is purely quantitative whereby online survey was used as a means of data collection. Table 2 depicts the design elements used for this study. Questionnaires were carefully prepared with the anonymity of the respondents safe guarded (See underlying data)16. This was ensured as no personal data identifiers were collected. Additionally, an ethics approval was obtained before recruiting participants for the survey. From primary and secondary Malaysian schools, 200 teachers were invited to participate, however only 131 teachers responded. The items were adopted and adapted from various theories and previous studies conducted by Mueller and Dweck6, Dweck8, Hakak et al.12, Eleftheria et al.14 and Gipps15. They were measured using the 5-point Likert scale, ranging from strongly disagree (1 points) to strongly agree (5 points). The odd Likert scale to give the survey respondents a choice to respond neutrally, was included. This was done to obtain evidence about a theme by adding a neutral response option for the respondents to select, should they refrain from selecting an answer from the two extreme choices. The scale offers five answer options. Table 2 depicts the research design components and their respective rationalizations.\n\n\nData analysis\n\nThe data for this study was analysed using the SmartPLS 3 software.\n\nThe measurement model evaluation is required to affirm the reliability and validity of the research model. The data attained from the questionnaires (See underlying data)16 were used to structure the measurement model of this study (Figure 1)\n\nIndicator reliability is assessed by ensuring that the factor loadings for each item is above 0.708. However, there is a satisfactory threshold whereby the values of each item do not necessarily have to be above 0.708. Table 3 affirms that the loadings for each item fall within the satisfactory value, thus indicator reliability is present. Internal consistency reliability is determined by the composite reliability (CR). As depicted in Table 2, the CR values for each construct are well above the 0.70 threshold, hence this affirms that the internal consistency reliability is satisfactory. Convergent validity is determined by the Average Variance Extracted (AVE). The AVE values for each construct must be above 0.50. The AVE for each construct in Table 2 is well above 0.50 and this signifies a satisfactory level of convergent validity for the study.\n\nAVE: Average Variance Extracted; CR: Composite Reliability\n\nDiscriminant validity is evaluated according to the Fornell and Larcker criterion, whereby an item must show a stronger loading on its own construct when compared to other constructs. Table 4 affirms that each item has a stronger loading on its own construct, therefore, discriminant validity is fulfilled.\n\nThe structural model evaluation is conducted to determine whether the hypotheses are supported by the data attained from the analysis. The structural model depicted in Figure 2 is attained after a non-parametric bootstrapping using a sample of 5,000 was conducted. Before assessing the path coefficient of this study, the coefficient of determination (R2) is explained. The value of R2 for this study is 0.627, which falls under the moderate category. This means that 62.7% of the total variance in Innovative Delivery is explained by Empathy, Thinking Process, Curriculum Enhancement and Gamifying Lessons.\n\nThe path coefficient for this study is depicted in Table 5. For the beta value to make an impact to the research model, the value must be at least 0.1 whereas the t-statistic has to be greater than 1.645 at an alpha level of 0.05 in order for it to be significant. Table 3 confirms that curriculum enhancement, gamifying lessons and thinking process have a significant positive influence in enhancing innovative delivery. However, empathy does not have a significant positive influence in enhancing innovative delivery.\n\nT-value significant at ≥1.645; P-value is significant at < 0.05\n\n\nDiscussion and conclusion\n\nThe study showed that the thinking process, gamifying lessons, and curriculum enhancement have positive significance for innovative delivery. However, the variable empathy was not supported and did not show a positive significant relationship. The absence of empathy among teachers can affect the educational process adversely. Empathy is a method of associating with others that shows you can comprehend that they are encountering something significant, even though you may not understand precisely how it feels for them17. Empathy is an essential advantage that can assist teachers by enhancing the driving factors on students’ behaviour. Thus, the link between teachers’ empathy and innovative teaching is essential and since the hypothesis for this study pertaining to empathy is not supported, it means that Malaysian teachers in predominantly primary and secondary schools lack empathy, which indirectly creates a large gap or power distance between students and the teachers themselves. This situation further enhances inability to deliver dry and uninteresting teaching and learning material which leads to hatred and disinterest among students in the subject. The current pandemic has made students more productive, independent, and proactive in being responsible for their learning. As such, the overall results of the Sijil Pelajaran Malaysia (SPM) 2020 or the Malaysian Certificate of Education, which is a national examination taken by all fifth-form secondary school students in Malaysia. have shown a sharp rise in passing and grades as compared to previous years18. This also indicates that teachers are no longer seen as mere content providers and knowledge givers, but as facilitators and support during difficult times. The lack of empathy among teachers must be addressed if teachers are exposed to DT workshops during their formal training and periodically as part of their learning development programme. The outcome of this study shows the aspects which need to be addressed by the Ministry of Education as well as the teachers in Malaysia. In addition, the outcome of this study may also assist in producing teachers who are well rounded in terms of mastering various teaching skills.\n\n\nEthics approval\n\nThe Research Ethics Committee (REC) of Multimedia University has granted the ethics approval for this research with the approval number EA2232021.\n\n\nData availability\n\nFigshare: Enhancing innovative delivery in schools using design thinking\n\nDOI: 10.6084/m9.figshare.1487187916.\n\nThis project contains the following underlying data:\n\nData file 1. The data attained from the questionnaire. This file is to be opened using the SPSS software.\n\nData file 2. Questionnaire used for this research.\n\nData are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Author contributions\n\n\n\nSharmini Gopinathan was responsible for the conceptualization, supervision, methodology and data analysis. Anisha Haveena Kaur assisted in the conceptualization, investigation, and data analysis. R. Kanesaraj Ramasamy provided resources for this study and explained the findings of the research. Murali Raman also provided the resources for the study (specifically for Design Thinking) and assisted in the direction of this research. All authors were part of the writing process. Sharmini and Anisha took on the responsibility to address comments by the reviewers.\n\n\nAcknowledgments\n\nThe authors would like to express their gratitude towards the respondents (teachers) who participated in the survey.\n\n\nReferences\n\nOxford University Press: Design. Retrieved from Lexico: 2021. Reference Source\n\nOxford University Press: Thinking. Retrieved from Lexico: 2021. Reference Source\n\nNaiman L: Design Thinking as a Strategy for Innovation. Retrieved from The European Business Review: 2019. Reference Source\n\nPlattner H, Meinel C, Leifer L: Design Thinking: Understand-Improve-Apply. Heidelberg: Springer, 2011. Publisher Full Text\n\nWarren CA: Empathy, Teacher Dispositions, and Preparation for Culturally Responsive Pedagogy. J Teach Educ. 2017; 69(2): 169–183. Publisher Full Text\n\nMueller CM, Dweck CS: Praise for intelligence can undermine children's motivation and performance. J Pers Soc Psychol. 1998; 75(1): 33–52. PubMed Abstract | Publisher Full Text\n\nBurnett PC: Teacher Praise and Feedback and Students' Perceptions of the Classroom Environment. Educational Psychology: An International Journal of Experimental Educational Psychology. 2002; 22(1): 5–16. Publisher Full Text\n\nDweck C: Mindset: The New Psychology of Success. New York: Ballantine Books, 2007. Reference Source\n\nAnderson RT, Neri L: Reliability-Centered Maintenance: Management and Engineering Methods. Essex: Elsevier Science Publishers Ltd, 1990. Publisher Full Text\n\nCambridge: Developing the Cambridge learner attributes. Retrieved from Cambridge International: 2011. Reference Source\n\nGopinathan S, Raman M, Subbarao A, et al.: The Role of Blended Learnning Technologies in Enhancing Student Engagement in Theory Dominant Subjects. International Journal of Creative Multimedia. 2020; 1(1): 64–69. Publisher Full Text\n\nHakak S, Noor NFM, Ayub MN, et al.: Cloud-assisted gamification for education and learning – Recent advances and challenges. Computers & Electrical Engineering. 2019; 74: 22–34. Publisher Full Text\n\nNah FFH, Zeng Q, Telaprolu VR, et al.: Gamification of Education: A Review of Literature. International Conference on HCI in Business. 2014; 8527: 401–409. Publisher Full Text\n\nEleftheria CA, Charikleia P, Iason CG, et al.: An innovative augmented reality educational platform using Gamification to enhance lifelong learning and cultural education. IISA 2013: Fourth International Conference on Information, Intelligence, Systems and Applications. Piraeus: Institute of Electrical and Electronics Engineers (IEEE), 2013. Publisher Full Text\n\nGipps C: Beyond Testing: Towards a Theory of Educational Assessment. London: Routledge, 2011. Reference Source\n\nGopinathan S, Kaur AH, Ramasamy RK, et al.: SPSS Survey Data for Enhancing Innovative Delivery Using Design Thinking. figshare. Dataset. 2021. https://doi.org/10.6084/m9.figshare.14871879.v1\n\nPeck NF, Maude SP, Brotherson MJ: Understanding preschool teachers’ perspectives on empathy: A qualitative inquiry. Early Child Educ J. 2015; 43(3): 169–79. Publisher Full Text\n\nChung N: 2020 SPM results best in past 5 years. Retrieved from Free Malaysia Today. 2021. Reference Source"
}
|
[
{
"id": "95936",
"date": "26 Oct 2021",
"name": "Paulo SImeão Carvalho",
"expertise": [
"Reviewer Expertise Physics education",
"teacher training in phusics",
"digital educational resources",
"experimental work"
],
"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 describes the role of design thinking that can lead to innovative teaching among teachers. In particular, it presents a study that seeks how several variables such as empathy, thinking process, gamifying lessons and curriculum enhancement, may have positive significance for innovative delivery. The study targeted 131 teachers from primary and secondary schools in Malaysia.\nI find this paper has great interest for teachers, although it concerns only Malaysian ones. The case cannot be extrapolated to other countries, but undoubtedly points out to real educational problems that should be seen very seriously by decision makers.\nConcerning the sample, it is not clear how many of those 131 teachers were from primary school and secondary school. As far as I know, the teaching goals, the contact hours and the involvement of teachers with their students may not be exactly the same for both categories of teacher, therefore the authors should provide separate analysis for both samples – even if, at the end, they conclude the results are equivalent.\nThere are some issues that could be clarified by the authors (page numbers refer to the pdf version):\nIn page 3, line 4 (Introduction), left column, the acronym VUCA is not used in the paper. I suggest to remove it, unless there is a specific reason to keep it.\n\nPage 4, line 4, left column: I would say that not only collaborative, but also cooperative learning should be recommended, as the latter involves students in the responsibility for finding solutions to the problems.\n\nPage 5, line 13, right column: instead of “the loadings for each item fall within the satisfactory value”, I suggest it should be added \"for the majority of items\" because as the authors recognize, there are some items that do not fulfill that condition.\n\nPage 4, figure 1, empathy variables: why is the sequence, from top to bottom, different from the other design components? i.e., why not E1; E2; E3; E4; E5 ? The same comment applies to Figure 2.\n\nPage 6, line 12, right column: alpha value, or p-value?\n\nPage 6, line 32-33, right column: the sentence “Malaysian teachers in predominantly primary and secondary schools lack empathy” is somehow exaggerated. This study is based only in 131 responses, which do not represent, in any way, Malaysian teachers. The authors cannot make such a generalization. This sentence MUST be reformulated to the local validity of this study.\n\nPage 6, line 36-38, right column: I don't see a direct correlation between the results obtained and the conclusion that “This situation further enhances inability to deliver dry and uninteresting teaching and learning material”. The authors should discuss better how they figure out such a correlation derived from their definition of Empathy. Their extrapolation is very broad and I don't think it has support in this investigation. Perhaps the authors want to rephrase it as a possibility that might occur, but not as an affirmative statement.\n\nPage 6, table 2, line 5: item “CE4” seems to be “CE5”.\n\nFinally, the reference list seems adequate to the study reported, and the English is of high quality.\n\nIn conclusion:\nI believe the paper is interesting for discussion about the influence of several parameters to innovative delivery in schools, taking for a particular example primary and secondary teachers in Malaysia. However, some topics could be clarified and generalizations should be avoided because the study is not vast enough.\nSo, I recommend this paper for indexing, but the authors must correct some errors and clarify the items mentioned first.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7488",
"date": "30 Nov 2021",
"name": "Sharmini Gopinathan",
"role": "Author Response",
"response": "(Page numbers refer to the pdf version of the article) 1. In page 3, line 4 (Introduction), left column, the acronym VUCA is not used in the paper. I suggest to remove it, unless there is a specific reason to keep it. -The acronym VUCA has been removed as it is not used in the paper. 2. Page 4, line 4, left column: I would say that not only collaborative, but also cooperative learning should be recommended, as the latter involves students in the responsibility for finding solutions to the problems. - A very good recommendation by the reviewer. However, as the statement was attained from a citation, we are not able to add it in the sentence as it will not reflect what was originally interpreted/meant by the author (of the citation). We shall take note of cooperative learning for future studies. 3. Page 5, line 13, right column: instead of “the loadings for each item fall within the satisfactory value”, I suggest it should be added \"for the majority of items\" because as the authors recognize, there are some items that do not fulfil that condition. - “Each item” has been replaced with “for the majority of items”, as recommended. 4. Page 4, figure 1, empathy variables: why is the sequence, from top to bottom, different from the other design components? i.e., why not E1; E2; E3; E4; E5 ? The same comment applies to Figure 2. - The sequence was automatically generated by the SmartPLS 3.0 software. As the figures were directly taken from the (measurement and structural) models generated by the software, we have decided to not alter it and retain the sequence the way it is. 5. Page 6, line 12, right column: alpha value, or p-value? - Alpha value (significance level). 6. Page 6, line 32-33, right column: the sentence “Malaysian teachers in predominantly primary and secondary schools lack empathy” is somehow exaggerated. This study is based only in 131 responses, which do not represent, in any way, Malaysian teachers. The authors cannot make such a generalization. This sentence MUST be reformulated to the local validity of this study. - The sentence has been changed to “Thus, the link between teachers’ empathy and innovative teaching is essential and since the hypothesis for this study pertaining to empathy is not supported, it means that the Malaysian teachers who participated in this study predominantly lack empathy, which indirectly creates a large gap or power distance between students and the teachers themselves”. This was done to avoid generalisation of the whole population. 7. Page 6, line 36-38, right column: I don't see a direct correlation between the results obtained and the conclusion that “This situation further enhances inability to deliver dry and uninteresting teaching and learning material”. The authors should discuss better how they figure out such a correlation derived from their definition of Empathy. Their extrapolation is very broad and I don't think it has support in this investigation. Perhaps the authors want to rephrase it as a possibility that might occur, but not as an affirmative statement. - Rephrased as suggested by the reviewer. 8. Page 6, table 2, line 5: item “CE4” seems to be “CE5”. - CE4 has been changed to CE5. 9. Finally, the reference list seems adequate to the study reported, and the English is of high quality. - Thank you. 10. Concerning the sample, it is not clear how many of those 131 teachers were from primary school and secondary school. As far as I know, the teaching goals, the contact hours and the involvement of teachers with their students may not be exactly the same for both categories of teacher, therefore the authors should provide separate analysis for both samples – even if, at the end, they conclude the results are equivalent. - 61 of the respondents are primary school teachers and the remaining 70 respondents are secondary school teachers. As this is not a comparison study between primary and secondary school teachers, we have decided to retain the current analysis as is it."
}
]
},
{
"id": "95938",
"date": "15 Nov 2021",
"name": "Achmad Samsudin",
"expertise": [
"Reviewer Expertise Science education",
"conception",
"conceptual change",
"misconception in physics",
"development of models",
"media",
"and instruments"
],
"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\nExplain in the abstract section the research questions used and the result. Describe the number of teachers for each school (primary and secondary schools). Describe what survey instruments were used? Open/close-ended, how many questions, using a Likert scale or something like that, etc.\nIntroduction\nIs there any previous research that discusses something similar? And what is the novelty of this research? Explain in this section. Add citations for your opinion. Is it necessary to use innovative delivery to benefit from learning outcomes? In the fulcrum of the study’s objectives, this section should serve as an answer to a research question, but why are the numbers different? It should only be the same number of research questions.\nMethods\nPut the design in the abstract. For respondents, describe the number of teachers for each school (primary and secondary schools). Explain why the SmartPLS 3 software is used in this study. If necessary add citations to strengthen it. Note in Table 1, there are 5 DT Phases (of course this section is an indicator in this study). However, why in Figure 1 do only 4 of the 5 phases exist? The missing piece is \"Prototype\", why is that? Same for Figure 2, why do only 4 of the 5 phases exist? The missing piece is \"Prototype\", why is that?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7489",
"date": "30 Nov 2021",
"name": "Sharmini Gopinathan",
"role": "Author Response",
"response": "Abstract 1. Explain in the abstract section the research questions used and the result. - Included in the abstract, as recommended. 2. Describe the number of teachers for each school (primary and secondary schools). - The number of teachers for each school has been added, as recommended. 61 of the respondents are primary school teachers and 70 of the respondents are secondary school teachers. 3. Describe what survey instruments were used? Open/close-ended, how many questions, using a Likert scale or something like that, etc. - The description of the instrument has been added. Questionnaire was used and there were 23 close-ended questions. A 5-point Likert scale was used. Introduction 1. Is there any previous research that discusses something similar? And what is the novelty of this research? Explain in this section. Add citations for your opinion. - We have included an explanation about DT in the education context, specifically in schools, whereby there is limited empirical research. 2. Is it necessary to use innovative delivery to benefit from learning outcomes? - Yes, this is much needed in the Malaysian context, especially with the sudden transition from face-to-face teaching to online teaching due to the pandemic. Teachers and schools are finding new and innovative ways to deliver their learning outcomes. 3. In the fulcrum of the study’s objectives, this section should serve as an answer to a research question, but why are the numbers different? It should only be the same number of research questions. - We have amended the research objectives to suit the research questions. The research objectives are as follows: 1. To determine if DT in the form of empathy leads to innovative delivery of curriculum. 2. To examine if DT can lead to new forms of thinking processes, gamified lessons and curriculum enhancement, thus leading to innovative delivery of curriculum. Methods 1. Put the design in the abstract. - Added. Included the use of questionnaire, number of questions and the Likert scale used. 2. For respondents, describe the number of teachers for each school (primary and secondary schools). - The number of teachers for each school have been added, as recommended. 61 of the respondents are primary school teachers and 70 of the respondents are secondary school teachers. 3. Explain why the SmartPLS 3 software is used in this study. If necessary add citations to strengthen it. - SmartPLS 3 software was used as it is able to analyse inter-relationships between variables, whereby single/multiple regressions can be stated (Hair et al., 2011). 4. Note in Table 1, there are 5 DT Phases (of course this section is an indicator in this study). However, why in Figure 1 do only 4 of the 5 phases exist? The missing piece is \"Prototype\", why is that? Same for Figure 2, why do only 4 of the 5 phases exist? The missing piece is \"Prototype\", why is that? - As per the Introduction section, “Prototype” falls under the sub-section “Gamifying Lessons”. We have described it as such: “Prototyping in DT leads to a new form of learning, which in this context refers to gamification”. References Hair, J. F., Ringle, C. M., & Sarstedt, M. (2011). PLS-SEM: Indeed a silver bullet. Journal of Marketing theory and Practice, 19(2), 139-152. DOI: 10.2753/MTP1069-6679190202"
}
]
}
] | 1
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https://f1000research.com/articles/10-927
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https://f1000research.com/articles/10-1290/v1
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16 Dec 21
|
{
"type": "Research Article",
"title": "A narrative inquiry into the resettlement of armed forces personnel in the Arabian Gulf: a model for successful transition and positive mental well-being",
"authors": [
"Richard Mottershead",
"Nafi Alonaizi",
"Nafi Alonaizi"
],
"abstract": "Background: The study sought to explore the lived experiences of individuals having served in the Armed Forces of Saudi Arabia, as they made the transition to civilian life and sought new employment opportunities.\n\nMethods: Researchers carried out qualitative research in the form of narrative inquiry. Narratives were collected from eleven in-depth interviews conducted in Saudi Arabia in 2021, allowed for insight into participant experiences. Existing literature on military retirement was also investigated. Results: Interviews were transcribed verbatim and analyzed concurrently using thematic analysis to identify patterns or themes. The researchers adopted thematic synthesis as an analytical framework though which descriptive themes from the literature on military retirement were generated. Overall, this approach allowed for the comparison of themes in literature with those of narrative interviews. Conclusion: The study identified challenges encountered by veterans during the resettlement and transitional phase from military to civilian life. There was a general consensus, however, that military life equips individuals with valuable skills that are transferrable to successful post-military employment, known as Positive Transferable Adaptability for Employability (PTAE), (Mottershead, 2019), which can greatly empower those making the transition. These findings led the researchers to develop a new model for veteran career paths that meet the contemporary employment needs of the Kingdom of Saudi Arabia: the REVERE Transition Model, which identifies six career paths.",
"keywords": [
"Keywords: Transition",
"Mental Well-Being",
"Resettlement",
"Retirement",
"Veteran",
"Saudi Arabia",
"Vision 2030"
],
"content": "Introduction\n\nService personnel who retire from the military (hereinafter referred to as “veterans”) have been shown to encounter very different experiences than people who retire from conventional civilian life, and for many veterans, the transition is replete with difficulties and challenges (Herman & Yarwood, 2015). Military retirement is a challenging life-transition that can severely impact personal identity (Beech et al., 2017) and sense of self, yet the lived experiences of this particular kind of transition are under-researched and not well understood (Bulmer & Eichler, 2017; Cooper et al., 2017). In the Kingdom of Saudi Arabia (KSA), there is a necessity to explore and establish new knowledge on this very subject. Given the significant financial resources invested in the KSA’s Armed Forces (Trending Economics, 2021), it is important that policy and practice align to create an effective and empowering plan for resettlement and transition to civilian life and employment. The authors believe that this plan will support and accelerate the KSA’s ability to achieve the nation’s Vision 2030 targets (Saudi Vision, 2021). The Vison’s aim sets out a blueprint for the country to achieve further economic and social success by 2030. This paper suggests that veterans hold key skills that can help to ensure a vibrant society, a thriving economy, and drive the ambitions of a nation based on effective governing. The purpose of this paper is to explore eleven veterans’ experiences of the transition from military to civilian life as a means of demonstrating that the way in which the KSA’s current system manages veterans’ transition to civilian life is illogical and unsustainable. The authors then suggest a workable solution to this issue that falls outside of current practice in the KSA.\n\nFinnegan et al. (2010) explain that military service provides a protective “family,” with a community based on shared values, experiences, and socializing. Once an individual has enlisted, the military lifestyle impacts all aspects of their existence. Service also presents them with certain incentives: guaranteed employment, a good and steady income, the potential for a healthy pension, and ample annual leave. Reasonable housing is also available, and when the individual is promoted, accommodation improves. Members are also well-fed, clothed, and are exposed to tremendous adventure, educational training, and physical fitness opportunities. Finnegan et al. also highlight the army’s role in providing status and structure, which for those who are seeking a way to hold their lives together, could be a major reason to enlist. The authors go on to explore the fear of losing these benefits in veterans whose alternative is to move into an increasingly fragile economy with uncertain workforce opportunities (Finnegan et al., 2010). This is of particular interest, as issues of employment uncertainty and reduced income are among the themes noted in the present study.\n\nThe reconstruction of one’s identity, as a result of training, socialization, and contact with military culture, allows individual to assimilate into military life. This process is referred to in Goffman’s seminal 1961 work, based on field work in the the United States, as “disculturation”. This involves the internalization of military culture with inculcation of habits, mannerisms, and language, as well as the breakdown of previously held moral boundaries and the assertion of an “adapt and overcome” ethos. Goffman (1961) notes that this ethos is evident in the presence of confidence, courage, and organization in military personnel, and in their suppression of fear.\n\nIn addition to the notion of disculturation, Goffman examines the process of joining a “total institution”, a place in which a group of people is actively isolated from the community at large and to which the new identity must adapt (1961). This process certainly occurs in the military context, and as Bradford (2006) global review finds, is more evident during initial basic training, where in its exaggerated form, the process of isolation can produce recruits who are not ruled by their own social and political order, but who are rather self-focused and institutionally blind to the Government or political leader in command. This indoctrination into a military regime, identified as a “self-mortification” process by Goffman, serves to create a new mindset and military identity (Bradford, 2006). Specifically, participants in Goffman’s study seemed to have established a new identity, which subsequently instigated some radical shifts in their “moral career,” altering their beliefs about themselves, others, and the world around them (1961).\n\nA sociological theory relating to the process of identity reconstruction is provided by Stevenson, who looks specifically at the United States military context. He corroborates the observations made by Goffman and Bradford, from the initial emergence of the individual into basic training, to the remodeling of identity and adoption of a new culture, language, and tradition, which can vary even between different military services (Stevenson, 2010).\n\nParkes and Prigerson (2013) explain that those exposed to military culture can experience such a deep sense of belonging to their military identity and life, that the transition to civilian life is often viewed as a loss. The authors describe the grief associated with the transition as an emotion similar to missing something of significance, and go on to explain that this sense of loss or grief can even occur as a result of losing a valued ability or role (Parkes & Prigerson, 2013). Parkes (1971) also describes a process, later expanded upon by Rahe (1979), of psychosocial transition in relation to such loss. In his work, Parkes (1971) warns of the dangers of institutionalization and of removing an individual from an institution in which they find comfort. Parkes and Prigerson (2013) state that during such transitions, that which is familiar can suddenly appear to have become unfamiliar. Previously established habits of thought and behavior no longer apply to the new external world, and as a result, confidence is lost within the individual’s internal world.\n\nRelevant to the present study is Tajfel and Turner’s Social Identity Theory (SIT), which is used to predict and explain certain behaviors between two or more groups. SIT states that an individual’s self-concept of personal and social identity influences their behavior and actions as they compare themselves to different groups (1986). Ashforth and Mael (1989) argue that this definition allows for an internal cooperative blending of identity, meaning that sense-making and establishing meaning occurs within the individual as they relate to the world around them—subsequently defining and locating their place within the wider context of the social environment. Hockey’s research into British military service personnel provides a concrete example of this: individuals belonging to the group of military personnel are, at their core, trained to be combat-ready through a process of physical and mental training—enabling them to respond to other groups, “threats,” with aggression and violence (1986, 2003).\n\nIn keeping with SIT and in relation to the current study, Abrams and Hogg (1990) would argue that the individual veteran should be able to locate and define themselves through an evaluation of the social characteristics of the group from which they derive their identity; they stipulate, however, that this process relies on first, defining other groups within their environment and how their identity merges into that perceived reality. According to Erikson’s 1968 seminal work, this can pose a challenge to the veteran whose self-understanding, formed through a perception of norms, attitudes, beliefs, feelings, and behaviors centered within their “ego,” is in conflict with their subjectively defined place within civilian society—a place defined by Brubaker and Cooper (2000) as their “social location”. Continuing along this line of reasoning, Ashforth and Mael’s (1989) research on SIT stipulates that an individual may have multiple roles and belong to numerous groups, thereby creating equally diverse social and personal identities. Of particular relevance here is that while these identities generally function in harmony with each other, when one set of values, norms, behaviors, and beliefs is incompatible with another, a conflict between opposing identities arises within the individual (Ashforth & Mael, 1989). This can provide significant insight into Saudi veterans’ transition to civilian life.\n\nThe literature described here indicates that the military identity is composed of resilient character traits forming a well-developed social identity. There is a notable deficit of references to a policy or practice for dismantling the military identity and allowing for the dramatic shift to civilian attitudes, norms, and feelings. This highlights the timeliness of the present study to examine veterans in the KSA and the need to help them disengage from their military identity and identify with their civilian peers.\n\nThe need to belong is also a feature of SIT. Tajfel and Turner (1986) explain that social identity consists of “those aspects of an individual’s self-image that derive from the social categories to which he perceives himself as belonging”. This claim is bolstered by the findings of Steger and Lopez (2011), who observe a continuing process to establish meaning through belonging. More specific to the current study, Barron, Davies and Wiggins (2008) identify comradeship and associated societal support to be crucial in promoting a sense of belonging for veterans. This is supported by Burnell et al. (2006) who cite the importance of comradeship in veterans returning home and transitioning back to post-military identities as civilians. It follows that there is a need to explore post-military identities further within the KSA.\n\nIt is evident from the literature on veteran identity, that at its core, is the sense of belonging to something, which extends beyond a uniform and an employment status. The idea of belonging is identified as being central to our understanding of how veterans are given meaning to their lives, and this sense of belonging is intertwined with their successful engagement in a new civilian life. Stillman et al. (2009) explain that social relationships are a necessity for individuals to acquire a meaningful life. Additional research by Lambert et al. (2010) hypothesized that it is by virtue of relationships that a sense of belonging is created, as they help develop identity and render life more meaningful.\n\nThe literature examined up until this point indicates that there is a need for an international strategy to improve the support available for veterans with mental health needs. Particular concern has been raised by Finnegan et al. (2017) over the fact that upon leaving the army, soldiers may face financial and employability challenges for which they may be inadequately skilled to overcome. It is possible, therefore, when considering the research of Finfgeld (2004), that this will inadvertently have negative repercussions on veterans’ mental well-being if there is the absence of an empowering peer-support system. The presence of veteran peer-mentors with a shared military identity could become a powerful therapeutic agent, as it could cross institutional divides and prevent future financial hardships through advice and guidance.\n\nSeligman’s Locus of Control Theory (2007) corresponds with a key theme that emerged from the participant narratives, as it describes the extent to which a person feels that they have control over the events in their lives, and subsequently their ability to cope. Research undertaken by Solomon and Mikulincer (1990) ascertained that those veterans with a limited or lack of focus or control, were more at risk of developing PTSD. In participating veterans’ accounts, control appeared to have been a key feature of the transitional phase from the Armed Forces to civilian life. There was evidence within their narratives of a link between a lack of control and despondency, that would ultimately result in a negative outcome. This negative outcome ranged from unexpected employment challenges and strife, to loss of identity. Through the thematic analysis of veteran narratives and reflexivity, it was noted that for those veterans who believed they had lost or been deprived of control appeared to develop, what Seligman (1972) identified as, “learned helplessness”. According to the authors, learned helplessness occurs in situations in which the individual has little control over their life, and stress and burnout become major concerns in daily functioning as a result. These observations highlight notion of helplessness as a potential focal point for efforts to help veterans cope with change.\n\nThe necessity to cope with change and to understand how veterans can be empowered is a crucial focal point within this this emergent theme. Veteran narratives ascribed meaning and importance to the identity formed through social interactions (shared beliefs, values, and the process of military indoctrination) that took place during their time within the military community. Further, afield, research by Finnegan et al. (2017) highlights the disproportionately high rates of depression experienced by veterans in comparison to other professions. It would appear that the military identity creates positive mental well-being but that a detachment can lead to a diminished self-worth and perceived control.\n\nThe seminal works of Bowlby (1969, 1980) explains that a state of separation forms the basis for explaining attachment disorder. Bowlby’s research concentrated on the separation of an infant from their mother, creating a state of anxiety for the child which then led to depression and apathy (1973). Relevant to this is recent research undertaken by Finnegan et al. which highlights how the British Army is predominately composed of young men, often from disadvantaged backgrounds, in which depression is a common mental health disorder. This pre-existing fragile mental state can only be exasperated by a transition to civilian life in what is essentially a state of separation from that which has allowed them to cope (Finnegan et al., 2017). Within the veteran narratives, there was a suggestion that there were signs and symptoms of depression as the realization of retirement and changing status and financial resources became evident. Finnegan et al.’s (2017) work argues that unless the stressors for depression are not better understood, the ramifications will be the incapacitation of supposedly physically fit individuals. The researchers further suggest that this must be related to the poor understanding of the relationship to the causes of depressive symptoms and imbalances with regard to access and treatment (Finnegan et al., 2017). The participants spoke openly about the difficulties and anxiety they had faced, along with other “problems” (evident in most cases as allusions to mental distress and poor mental health but not always articulated as such), and that they felt that civilians struggled to understand the unique stressors associated with this loss of belonging to the Armed Forces. This self-awareness highlights the mindfulness and self-understanding that the participants had of their reality.\n\nGoffman’s (1963) presentation of self-theory can be discussed in terms of veterans, and states that self-understanding, as formed through self-perception of norms, attitudes beliefs, feelings and behaviours centred within ‘self’, is in conflict with their subjectively defined place within civilian society. This can pose a challenge to the military veteran when viewed through the seminal work of Erikson (1968), if their self-understanding, as formed through self-perception of norms, attitudes beliefs, feelings and behaviours centred within ‘ego’, is in conflict with their subjectively defined place within civilian society. A place defined by Brubaker and Cooper (2000) as a ‘social location’.\n\nThe corresponding author’s previous research was identified within the 2014 Veteran’s Transitional Review by Lord Ashcroft, the UK’s first transitional review. This government review highlighted that the process of re-entry into a civilian identity can be challenging for some veterans and the evidence appeared to suggest that those veterans lacking in understanding of the transitional process, struggled to adapt to new roles and identities. Goffman (1963) stipulates through his dramaturgical analysis approach, that an individual may have multiple roles and belong to numerous groups, therefore creating equally diverse social and personal identities. The literature would suggest that the transitional process from military life creates challenges around self-understanding, as civilian values seem to encompass military values in certain circumstances.\n\nThe study will seek to draw parallels between these themes of identity reconstruction, the dangers of displacement and the draw of military service, found in existing literature, and the themes that emerge from our study participants’ own narratives. The study presents the rationale for a specific approach that encapsulates the complexity of capturing the lived experience. This approach considers a new source of knowledge, the veterans’ perceptions. These capture both the individual and social experiences of transitioning from military service to civilian life. This study is an attempt to create an understanding through the voices of those that have served KSA, and an effort to empower them within the Saudi Vision 2030.\n\n\nMethods\n\nAll participants provided written informed consent and that their anonymised data could be used for the purpose of this study. Ethical approval was granted via the authors’ institutions.\n\nThis study provides a methodological focus which aims to provide a new understanding of the veterans’ (participants’) lives as they experienced transition from military personnel to civilian. Therefore, the study adopts a qualitative approach. Qualitative research involves the exploration of social interactions between individuals in specific situations and identifying meaning from these interactions (Denzin & Lincoln, 2005). Qualitative researchers aim to understand the world from the perspective of the research participants, and they do this using various research methods (Denzin & Lincoln, 2005). Our study used semi-structured interviews which collected narrative data from participants and allowed for observations of their behaviour in specific social settings. There were eleven participants in total who had all served in the KSA Armed Forces (see Table 1).\n\nNarratives provide both a practical and holistic approach to collecting information about another individual’s life, which aids others to glimpse inside their perceived reality and widen our understanding of human existence. In selecting a narrative methodology, the research study sought to allow the veterans to tell their life stories and increase knowledge of their lived experiences of transition from the KSA Armed Forces. According to Bochner (2015), allowing individuals to tell their life stories enables them to make sense of their lives by placing meaning to their experiences in a tangible form. Atkinson (1998) concurs when explaining that narratives allow for the generation of rich subjective meaning that allows individuals to present their life events as they wish them to be presented. Plummer (2001) explains that narrative researcher can enable the participant to create the frame of reference for the telling of the life story and the method highlights the interactions that exist between the individual and their social world. Given the need to create a working strategy to empower KSA military veterans, this methodology was seen to be crucial.\n\nLocal COVID-19 restrictions were adhered to for face-to-face interviews or were conducted online to collect the veteran’s narratives from within the Kingdom of Saudi Arabia in 2021. A snowballing sampling method was chosen as a recruitment strategy. Initial participants were selected via NA’s social networks based within Saudi Arabia. This sample technique provided a purposive approach to overcoming the problems associated with sampling this population. Lee (1993) explains that the snowballing technique is particularly useful when attempting to access participants who may be reluctant to share their life stories. The researchers relied upon the assumption that a bond or link exists between the initial sample and others in the same target population, which allowed for a series of referrals to be made to the researchers from within a circle of acquaintances (veterans) as advocated by Berg (1988). Interviews were then conducted at a time and place of the choosing of the participant. Standing (1998) highlights that the researcher have an opportunity to build rapport with participants who have been introduced by other participants, who have already explained the objectives of the study and the way in which it deals with consent and confidentiality.\n\nThe process of collecting the narratives occurred between May to September 2021. Interviews were conducted using a semi-structured format, incorporating an interview schedule devised to incorporate themes identified from the thematic synthesis of the literature. Bachman and Schutt (2013) recommend this approach, as it ensures that all dominant themes and main areas of interest are covered, guaranteeing consistency between interviews, whilst also maintaining sufficient flexibility to allow for unanticipated themes to be identified and discussed.\n\nThis approach was adopted due to the evidence provided by Bryman (2012), who stated that this strategy encouraged interviewees to fully communicate their experiences through open, free-flowing accounts that could then be explored with prompts and open questions. As suggested by Bryman (2012), this avoids inadvertently leading or influencing participants in their responses and allowed the study to gain a nuanced understanding of the issues under investigation. The questions were the same for online and face-to-face interviews. As recommended by Bryman (2012), a digital recorder was used to record interviews that were face-to-face and the recording facility on a video-conferencing platform, Microsoft Teams, assisted greatly in the interview process. This process allowed both the participant and researchers to relax and converse more freely without the need for extensive notetaking, which can cause distraction and inhibit communication flow.\n\nThe narrative interviews were analysed using thematic analysis as utilised by Braun and Clarke (2006). Braun and Clark recommend a thematic analysis be adopted as part of multiple qualitative methods. Thematic analysis is a process of visualising and encoding qualitative research material through the formation of codes and themes. As the sample for this phase of data analysis is relatively small (9), it was decided that manual examination of the data and recurring themes would be appropriate. The use of NVivo (Hilal & Alabri, 2013) was rejected in line with the recommendations from Silverman (2005), who argues that software programmes for qualitative research are not a substitute for researcher data analysis. Boyatzis (1998) describes a theme as a pattern located within the data that either partially describes and gives order to a feasible observation, or in its entirety, is able to interpret and therefore give meaning of a phenomenon. His process of analysing the narratives was selected due to its flexible and straightforward technique, which created an evidenced theoretical framework that could provide insight into the lived experiences of the veterans.\n\nIn utilising a thematic approach in analysis, Braun and Clarke (2006) insist there are several phases of data analysis. This multi-stage approach as advocated by Braun and Clarke (2006) lends itself to a constructionist framework as suggested by Burr (2003). Burr suggests that this approach allows for analysis to include what is unique to a participant, what is shared amongst participants, a description of the experience, an interpretation of the experience, a commitment to understanding the participant’s point of view and lastly, a focus on personal meaning-making within a particular context. The narrative interviews post-recording and transcription were analysed within a Braun and Clarke (2006) 6-stage model.\n\nPhase one included a repetitive reading of all the narrative transcripts. In this research study, the researchers began by reading the interview transcripts several times. This repeated reading allowed the researchers to enter into the veteran’s world and ‘listen’ to them as they gave voice to their beliefs and experiences. At this point, it was decided that the coding for the participants’ interviews would be numerical and a pseudonym would not be used to identify them. The rationale for this decision was based on the belief that the researchers could actively listen to the voices and remember the interview with more clarity.\n\nThe researchers believed that by using numbers to code the participants’ identity, there would be a continuity of information from the recordings of the interviews through to the writing up of the transcripts and the notes associated with these interviews. If the coding had been changed to use pseudonyms in the middle of the analysis, it is believed that some of the unspoken meaning of the participants’ experiences would have been lost. Also, clear identification was required in order to allow for in-depth analysis and data triangulation between the participants narratives. Continual use of reflexivity ensured that this interpretation occurred without any undue prejudices, stereotypes or personal attributions from the researcher’s perspective.\n\nSuresh and Chandrashekara (2012) explain that determining the optimal sample size for a study guarantees an adequate ability to detect a degree of significance and is therefore, a critical step in the design of a planned research proposal. Guest, Bunce and Johnson (2006) argue that determining a sample size typically relies on the concept of saturation, meaning the point at which no new information or themes are observed in the data. Malterud, Siersma and Guassora (2016) suggest that there are different sample sizes depending upon the research. Mason (2010) suggest that smaller sample sizes can be useful where a detailed exploration of the phenomenon from several different perspectives can be highly beneficial. Malterud, Siersma and Guassora (2016), however, suggests that there is no exact number and it depends on the individual study and when data saturation has been achieved. Within this study, the researchers ascertained that saturation had been met with the nine participants.\n\nThese prejudices, stereotypes or personal attributions were believed to arise from using aliases. When initially the notion of coding was considered, fictitious names were assigned and a list of nine names was constructed. However, each name had a specific meaning or connotation associated with it to the researcher. It was believed that these connotations would be a barrier to the ability of the researcher to be empathic and to immerse themselves into the participant’s world. In effect, while analysing and interpreting the data, the researcher could ‘hear’ the participant’s voice and did not want that voice being ‘confused’ by the voice of someone else that the researcher associated with that pseudonym. At this step, the intention was to focus directly on the veterans and become accustomed to the content of the life stories, the pace and flow of the interview and the relationship between researcher and veteran (participant).\n\nThe second phase focused on notetaking of any information within the data that appeared to be relevant to the research questions and amalgamating the thoughts and beliefs from the veterans. This was a more administrative step than the previous step, in that it looked at writing up the life narrative interviews into transcripts and reviewing the written text, in order to affix tenuous links from the data, culminating in beginning the process of clumping the data into codes and subsequent themes (Braun & Clarke, 2006). For this part of the process, the researcher printed off copies of the transcripts and on each individual transcript, began a line-by-line analysis of the content and then made handwritten reflexive notes in the margin. These notes focused on any pertinent information and used specific key words to identify this information with different coloured highlighting for the codes and emerging themes. At this stage, the notes were mainly descriptive with meaning to the individual explored superficially and not to any depth. Miles and Huberman (1994) suggests that these initial notes should include a description of the content, selecting key words, focussing on language and being aware of conceptualisation of how the participant makes sense of their experiences. This initial process was repeated several times with new documents printed off, updated and re-read, allowing new awareness of the data to be made by the researcher. These exploratory notes were then used to underpin the next stage in the process.\n\nPhase three identified themes that emerged from the interviews and were further analysed in more depth. The exploratory notes made in phase two were used to create new documents in order to develop emergent themes as Braun and Clarke (2006) suggest the focus moves in this phase from the transcript itself to the notes created by the researcher. Again, as for phase two, the documents were printed off several times, each time the notes being refined, and descriptors changed or modified as required in light of how the researcher began to enter into the world of the veteran in more depth. There was, however, a cyclical process that emerged here for the researchers where the focus moved from notes made to an original text as the depth of interpretation increased. At this step the handwritten notes in the margins expanded from specific key words as used in phase one to longer descriptive phrases.\n\nThe emphasis in this phase moved slightly away from the veterans-led representation of the data to a more researcher involved enquiry as the data was starting to be analysed. Within this phase, a series of corresponding themes started to emerge from participants narrative interviews and information relating to these themes was colour coded in the transcript documents. By this phase, the data set had become larger with more detailed information to be analysed. Braun and Clarke (2006) suggest that in this stage, the transcripts are de-constructed for analysis and it is possible to establish a thematic map. During this phase, the researcher started to think about the relationship between codes, between themes, and between different levels of themes (e.g., main overarching themes and sub-themes within them).\n\nPhase four signals part of the re-constructing stage and in essence, are explorative in that the aim is to link any connections between themes and a decision made to include or exclude material. In this step, in some instances, phases one to three were repeated. For Patton (2005), the key focus in this phase is discovering patterns and connections between emergent themes. As advised by Patton (2005) the researcher adopted a dual criteria for reviewing the emerging themes through a process of internal homogeneity and external heterogeneity. This is advisable in ascertaining similar themes across the veteran sub-group. Boyatzis (1998) advises that data within themes should cohere together meaningfully, whilst there should be clear and identifiable distinctions between themes. At this point on the analysis phase, the use was also made of a large whiteboard to make the handwritten notes more ‘visible’ to the researchers. The researchers would communicate via videoconferencing and discuss the overall view of the data and emergent themes. This specifically allowed the ‘movement’ of information from one theme to another as it became apparent some quotes aligned more with certain themes than others. If the researchers considered that some of the themes were irrelevant or did not fit in with the research questions, then these were excluded.\n\nAt this point in the analysis process, the sub-themes started to develop into main themes. By utilising a whiteboard, a matrix was constructed with the veteran identification code across the top (1 to 9) and the main themes on the left-hand side. The phrases from the transcripts were used in a simplified form to contextualise the sub-themes. This restructuring and reconsidering of the interpretations echo the iterative nature of thematic analysis.\n\nPhase five according to Braun and Clarke (2006), requires the start of the whole process again, however this time looking at the next participant’s transcript (in effect for this research study this process was repeated nine times). However, for this study phase, five to a certain extent was not utilised in the way Braun and Clarke (2006) advocates. Phase five in this study was integrated earlier into the analysis process, as each transcript was part of a cyclical process where some interviews were more detailed and contained more vibrant and emotive content, whilst others were shorter with less involved content. Each individual transcript was subjected to the same four previous phases as outlined above and suitable care was taken to ensure that each individual veteran’s transcript was considered discretely within this process. Each of the veteran’s experiences were considered primarily as an account of how they contextualise these experiences and explain them in their own terms and expressions, in effect, what these experiences of transition mean to them.\n\nThe final phase, phase six, according to Braun and Clarke (2006) requires detailed examination of all the emergent themes from all the transcripts and formatting this in a suitable way. Again, this study deviated from the guidelines from this step. For this study, phase six was a re-visitation of all the information gleaned from the narrative transcripts. In this stage, the emphasis was ostensibly focussed on the interpretation of the data. It was at this point, that the sub-themes were investigated in far greater depth. From this in-depth analysis, several issues arose. From exploring the transcripts from a deeper interpretive stance, it was observed that many of the sub-themes inter-linked and were present within both the veteran’s narratives.\n\nIn this final phase, this inter-linkage of the main themes between the participants became more prominent. The names of the main themes were changed several times in phase six in order to represent the content of that theme and the shared relevance. At this point in the analysis, it also became apparent that within some of the individual quotes from the veterans’ transcripts, there were sub-themes that could be attributed to more than one main theme. The decision was made to include these into the separate sub-themes even if replicated, however they would be interpreted and analysed within the context of that main theme. The emergent themes were then placed in an order that was logical and coherent to be explored further by the researchers.\n\nFollowing Braun and Clarke’s (2006) recommended process of thematic analysis of the narratives, numerous words and phrases (codes) emerged that held at their core, a meaning that extended beyond a uniform and an employment status and established an understanding of the reality of life for the study’s participants. The researchers were the only individuals with full access to the recorded narrative interviews and produced transcripts throughout the length of the research study. Each audio recording was password protected, was never duplicated and once the full transcription of the narrative interview was completed, the audio recordings were destroyed. Hardcopies of the transcripts were stored. The researchers would analyse extracts of each other’s interviews to ensure that findings were supported by the data and therefore a true representation to aid accurate and promote rigour. It was necessary to omit quotes and de-identify information pertaining to specific military units in order to guarantee anonymity and confidentiality.\n\nThe first author is a veteran and mental health nurse and the second author is currently serving as a military nurse for a country within the Gulf region. There was therefore a need to adopt reflexivity as an essential approach to augment the trustworthiness, integrity, and credibility of the studies professional use of self, to explore the participants’ understanding and interpretations of their experiences. The use of reflexivity seeks to elicit a greater depth in responses from participants aided by the researchers own former and present military identity and thoughtful use of prior theory and researcher expertise, as advocated by Higate and Cameron (2006). Moustakas (1994) advocates that interpretations would be understood to be a collaboration between the researcher and the participant, in order to bring out underlying conditions and hidden objectives of the phenomenon. Atkinson (1998) and Plummer (2001) also argue that communities are dominated by the voice of the dominant group, whilst the knowledge of ‘others’ outside of the group can go unheard or unnoticed.\n\nFinlay (2002) describes reflexivity as “thoughtful conscious self-awareness,” on the part of the researcher. This process was found to be enlightening for the researchers as an awareness became embedded within the researchers of a mindful evaluation of the participants’ responses, intersubjective dynamics between the two prominent identities (military and emerging civilian identity) and subsequent experiences. As nurses, reflection is embedded within effective practice and so often diffuses into parallel aspects of associated life. Meaning, that reflection can become engrained within a nurses life. For the researchers of this study, reflexivity involved a shift in the understanding of how we construct our knowledge from data collection to something objective.\n\nAccording to Tanggaard (2008), within qualitative research, it is recommended that narrative accuracy checks be undertaken to ensure that a high degree of accuracy, credibility, validity and transferability are established and maintained. The researchers cross-checked with participants the transcripts and their stories to ensure that it was a true representation and interpretation of what they had discussed. Cohen and Crabtree (2008) acknowledge this process within their own research and add that this approach can prevent personal biases from being included within a qualitative study. Higate and Cameron (2006) highlight the risk of the possible presence of pre-conceived notions for military researchers studying a former military population. Therefore, reflective practice was undertaken between the researchers who would review the data to ensure that the data was accurate and unbiased.\n\n\nResults and discussion\n\nMilitary transition is simply the change from military to civilian status. Far from simple, this can be a move from active duty to veteran or to retired life, but for many it is the beginning of a whole new experience. Table 2 outlines the four main themes that emerged from the data analysis.\n\nThe first theme emerged from narratives in which participants described their experience of the moment their retirement was announced. Participants spoke about their reflection on the concept of retirement and their level of readiness for the forthcoming chapter in their lives. Although they had varied experiences, most veterans felt unprepared for their retirement, which proved to be a challenging step as it was a difficult concept for the majority to grasp. Some experienced feelings of inadequacy and fear in relation to being unsure of how to begin this phase of their life. They had fears and worries about an unknown future and the cessation of an active work life. Military culture had also impacted veterans’ views of themselves and the world, leaving some feeling lonely and deeply sad. Certain individuals described life as being “unbearable” without their uniform, and others stated that coping was an ongoing process that disproved the expression “time heals all wounds.” Being forced to retire led to depression in some veterans, precisely because they did not have the option to refuse it.\n\nParticipants spoke about how scared they were after their retirement, as the uniform gave them an extra boost of confidence. Some asked themselves, “Am I going to lose people’s respect without (the uniform)?”. The military environment creates an association in the minds of military personnel between the uniform and empowerment. Such an association is difficult to undo and can leave a lasting impression after retirement. It leads to questions like, “What am I going to do after retirement?” and “How is life going to be without the uniform?”. While most veterans try to keep working after retirement so they can still feel active and productive, they still feel insecure about doing “normal” jobs; as they miss the feeling of empowerment that a uniform affords. This inherent need to belong for the military veterans, is consistent with the themes in previous research literature, of a continual effort to establish meaning through belonging. Indeed, whilst transition into a civilian role involves identity reconstruction, the veteran relies on comradeship and associated societal support to cope with change. This is of importance, as comradeship supports the transitioning back to post-military identities as civilians and to offset dangers associated displacement and loss.\n\nThis theme emerged in instances when participants described their experience at the beginning of their retirement journey and how it had a considerable impact on their family’s financial position. The majority were concerned that the financial allowance they would receive was not sufficient to cover their basic needs. This experience of financial insecurity was for many their first exposure to this loss of control and created uncertainty for their future. They had become reliant on the security offered by their military employment but recognised a need to establish new ways to regain control.\n\nWhile many veterans look forward to leaving behind the structure and rules of the military, those who have transitioned usually experience a loss of control and purpose, often identifying this loss as the biggest challenge. Participants found it challenging to find a suitable job in civilian life, and had difficulty performing simple tasks. Many of the participants commented that they had never been taught how to “write in a proper, professional manner” while in the military and that they had never participated in administrative work at any point in their military life.\n\nA number of participants felt that they should have had better training in basic skills required for civilian jobs prior to retirement. For example, veteran one viewed military culture as a commitment to do things properly and to do them well, and to always be prepared for what might happen next, except retirement.\n\n“Honestly, I am not prepared just retiring from the military after twenty years. But unless you’ve been there in my shoes, you don’t really totally understand. However, I have been trained to follow commands. I guess discipline and responsibility so I am accepting my retirement.”\n\nIn addition to soft skills, veterans also described how they did not learn the importance of proper communication and decision making in situations that required appropriate and professional communication. Some reported that the level of skills they possessed was limited, as there were many activities they were not permitted to practice while serving in the military. Some felt that in their new jobs, they were only entrusted with simple tasks that they already knew how to execute. One participant stated, “some managers […] underestimate us by giving us small tasks […] this is very frustrating.”\n\nThis description indicates that certain managers do not provide veterans with an opportunity to develop professionally. It was this feeling of being unappreciated that affected certain participants’ self-confidence. However, some described how they worked within such constraints to create maximum learning opportunities for themselves, adopting a more proactive approach. One veteran stated, “I am still young and (am) actually considering (taking) some courses at the university.” Overall, however, veterans mentioned loss of purpose and identity as the biggest obstacle faced during transition—and the most difficult one to overcome.\n\nParticipants discussed their thoughts on more effective retirement plans, given the feeling that they had not been adequately exposed to skills which would help them to cope with retirement. The most common suggestion was for better cooperation. Other participants explained that, in order to feel confident to undertake their own business, they would require a sense of financial support and security. The military has, to some extent, acknowledged the difficulty associated with the transition from military to civilian life. Some participants demonstrated self-understanding by acknowledging their over-reliance on their military life and experiences and at times, preoccupation with past stories which still had an influence of their sense of self, that did not end with their retirement from military service. Memories are an essential part of everyday personal and professional life. The participants demonstrated their awareness of how their life and its events have had a major role in shaping their individual characteristics. The veterans spoke of how their military experiences have influenced their establishment of self and who they were but also how this had extended to their families.\n\nThis study aimed to explore the lived experiences of eleven veterans, to develop a rich conceptual understanding of their transition from military to civilian life. This last theme emerged from perspectives on their overall journey after retirement. The first theme related to the participants’ thoughts at the moment of retirement, and highlighted the fact that most veterans lack the ability to be flexible and overcome the difficulty of leaving their previous life behind to start their new journey. The narratives illustrated the veterans ability to “bounce back” from difficult experiences, and their military experience appeared to have equipped them with an enhanced level of resilience:\n\n“With the absence of professional planning, actually it is not easy unless otherwise veterans have their own network who they can approach on a personnel level. This helps with coping with change but more can be done by veterans department to introduce veterans and highlight their competencies. Resilience is important but … opportunities help us to cope with the change”. Many of us are attached to our military self … we just need to pass this over more easily into this new life, otherwise we feel like we are not in the driving seat …”.\n\nThis narrative illustrates the attachment to the military identity and the sense of belonging that the veterans still feel towards that identity. This can create a sense of a lack of control in coping with change. The veterans attribute the establishment of resilience from their military training. Unlike some traits that people are born with, resilience is something that is learned. It involves behaviors, thoughts, and actions that are learned and developed throughout life. Some veterans expressed how it was difficult for them to find a job, as most jobs require a minimum of two years of experience. Others wanted to complete their education.\n\nIn this theme, participants provided insights into the barriers encountered during their professional journey. In addition, developing trust among other people plays an important role in shaping a future career, and although veterans’ overall experience was positive in this respect, some reported negative experience centered on a lack of trust. This consequently had an impact on an ability to cope. Participants also spoke about the education program that they had completed and how it did not prepare them sufficiently for the reality of civilian jobs. After leaving the military, the participants considered themselves civilians. However, they also expected to be treated as respected veterans who had served the country—and be accorded the responsibilities that accompany this role. It was also clear from all of the interviews, that a lack of proficiency in English makes communication in today’s world difficult. The challenge of working across a language barrier was the most commonly mentioned challenge among all respondents and obstacle in coping with change.\n\nThe proposed model (Figure 1) is an adaptation of the Positive Transferable Adaptability for Employability (Mottershead, 2019) model. The findings of the study, encapsulated within the narratives establishing the four emergent themes, led us to develop a new model to help support a career path that meets contemporary employment needs. The REVERE Transition Model identifies six options for ex-service personnel:\n\n(1) Relax: This option maybe the most common choice after retirement.\n\n(2) Education: Academic study or professional development.\n\n(3) Volunteer: Volunteer with children, teach, or coach sports.\n\n(4) Entrepreneur: Self-employment or owning a business.\n\n(5) Rehired: Retired military personnel often show leadership skills based on the discipline and training gained in the military, which are ideal to certain civilian careers.\n\n(6) Extend: Extension of military service be made by the head of office where strong justification exists, and this happens very rarely.\n\nThe REVERE model has been created with a strategic alignment to Saudi Vision 2030. It creates a dovetail between the potential and ability of KSA veterans and the aims of the Vison 2030, to diversify the economy and to meet the growing ambitions of the nation.\n\nThere is a need for further qualitative narrative research. This study has drawn upon the rich history of narrative methodology to contribute to the research of veterans in the KSA making the transition to a civilian life and identity. Further research into the areas of study listed below are seen by the researchers as necessary to achieving greater insight into the impact of transition and resettlement. This research is also necessary to the potential use of veterans’ skill sets to meet Vision 2030 target. These three suggested areas of study would be incorporated into a national Career Transition Partnership (KSACTP) that would establish a resettlement program, designed to aid veterans as they enter the civilian job market and to make a successful transition to achieve the wider vocational needs of the KSA, that are aligned to 2030.\n\n1) Psychological: Retiring military personnel will need support that recognizes the psychological impact of transition and resettlement on the individual and their family. A positive transition would take into account long-term exposure to a total (military) institution and have mechanisms in place to recondition veterans’ identity and expectations of civilian life and employment.\n\n2) Social: Relatives and or friends should be empowered to participate in the transitional process. The importance of creating a network for retired personnel was evident and seen as a crucially important peer-support initiative. The network aided them to share experiences and emotions, exchanging informational support, and well-being and emotional support that was enhanced via the shared lived experiences.\n\n3) Financial: The study recommends the reduction of the retirement term to 30 years of service, similar to the civilian pathway. Currently the service requirement is 35 years before retirement, and this can prove difficult to achieve. The study recommends a review of the current practice of pension calculation and the implementation of a future retirement plan for new troops, so that they may effectively plan their future earlier on. Career advice and preparation for a successful financial transition could be provided by veterans enlisted to mentor the next generation entering the KSA’s Armed Forces.\n\nThe findings of this study do not claim generalizability, having emerged from one geographical region and one homogeneous sample providing their subjective lived experiences, together with the researcher’s own interpretation of them. Undoubtedly, the researcher’s own subjectivity, lived experiences, and research interests may have inevitably influenced the interpretation of these findings as highlighted by Blaikie (2007). However, precautions were taken to limit the impact of this bias where possible, by adhering to a clear and robust methodological framework. Given the deficit of knowledge in this area, while modest, this study represents insight into an under researched topic within the region.\n\n\nConclusion\n\nFour key themes emerged from the research carried out as part of this study, that paralleled themes in existing literature. In narratives of the immediate impact of retirement, participants identified their attachment to the military uniform, which subsequently limited their control and increased their financial stress. This has a direct impact, if only temporary, on their mental well-being. Self-understanding and coping were the most common themes that emerged in narratives of the transition to civilian life. Participants highlighted a major concern regarding a lack resources to help them with this transition but acknowledged that there military skill set was a positive resource that they used to establish resilience and positive mental well-being. In response to this, we have developed the REVERE Model which has the potential to coordinate the strategic integration of veterans into wider society by presenting six options for post-military life. Furthermore, the researchers believe that the mobilization of the veteran community could be a rallying call to meet and the Kingdom of Saudi Arabia’s ambitions of Vision 2030.\n\n\nData availability\n\nData cannot be shared publicly due to potentially identifiable information. Data will be made available to reviewers or readers via the corresponding author.",
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London: Sage; 1998; 186–202.\n\nSteger MF, Lopez SJ: The pursuit of meaningfulness in life. Lopez SJ, Snyder CR, editors. The Oxford Handbook of Positive Psychology. 2nd ed.Oxford: Oxford University Press; 2011.\n\nStevenson RJ: Organisational Reaction to Social Deviance: The Military Case. New York: Algora Publishing; 2010.\n\nStillman TF, Baumeister RF, Lambert NM, et al.: Alone and without purpose: Life loses meaning following social exclusion. J. Exp. Soc. Psychol. 2009; 45(4): 686–694. PubMed Abstract | Publisher Full Text\n\nSuresh KP, Chandrashekara S: Sample size estimation and power analysis for clinical research studies. Journal of Human Reproductive Sciences. Jan-Apr. 2012; 5(1): 7–13. PubMed Abstract | Publisher Full Text\n\nTanggaard L: Objections in research interviewing. Int J Qual Methods. 2008; 7(3): 15–29. Publisher Full Text\n\nTajfel H, Turner JC: The social identity theory of intergroup behaviour. Austin WG, Worchel S, editors. 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}
|
[
{
"id": "115477",
"date": "04 Jan 2022",
"name": "Michael Robert Phillips",
"expertise": [
"Reviewer Expertise Human and Physical Geography"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting article that has contemporary and future relevance for post-military service and resettlement. Although focused on Saudi Arabia, results and conclusions will inform international resettlement strategies for veterans retiring from a military career. It is well written, argued from fundamental positions, and provides an interesting study of mental health. By assessing four themes results showed challenges and immediate impacts of retirement from the military. The authors used tried and tested techniques, including grounded theory, to make excellent contributions to the literature, e.g. thematic analysis and REVERE Model. In my opinion, the manuscript has many strengths including the provision of a widely applicable method for assessing change. Importantly, it has the potential for incremental progress towards a successful transition and positive mental well-being for resettling armed forces personnel.\nI don't know if it is journal policy, but I would prefer the Abstract to be written as a narrative without being broken down into Sections. Also, it is not usual to include references in the Abstract.\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": "7673",
"date": "06 Jan 2022",
"name": "Dr. Richard Mottershead",
"role": "Author Response",
"response": "Dear Professor Phillips, On behalf on myself and the co-author we would like to thank you for taking the time to review our research. In response to your query over the format of the abstract, this is the proposed style as directed by the journal which we followed diligently. Again, thank you for your peer review. Dr. Richard Mottershead"
}
]
},
{
"id": "115475",
"date": "06 Jan 2022",
"name": "Celia Hynes",
"expertise": [
"Reviewer Expertise Military veterans / 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\nEditorial Note from F1000Research – 6th January 2022:\nThe assigned status of this report has been updated from Approved with reservations to Approved at the request of the reviewer. No changes have been made to the text of the report.\nThank you for inviting me to review this paper which I found very interesting. The paper considers the challenges of transition for military personnel in the Kingdom of Saudi Arabia and this study makes the outcomes comparable to other countries regarding the transition from military service. In particular, the link back to the work of Goffman and also Social identity theory is very good with of course the link to attachment theory.\nI found the abstract clear and I am familiar and comfortable with this style.\n\nYou will note I have ticked partly for current literature as some of your references are quite dated and there have been more recent papers on transition experience. See for example the Forces in Mind Trust.\n\nAlso to note that two of your references were not listed - Finnegan et al., 2017 and Finlay 2002. Further, there are spelling errors for example in the introduction line 9 'Vision' and there are other minor ones so a good proofread is required.\nOverall the design is good with justification given for the sampling choice and the measures taken during the pandemic for interview etc. Data was also collected over a short period of time so again this approach would be necessary.\nThe quotes given within the themes - I can only see two - and these are very small font compared to other text. I would recommend maybe at least one quote per theme. Or remove them and provide overarching, as you have in the others such as 'participants spoke about etc.'\nThe REVERE model is good, refreshing, and widely applicable. Recommendations appear achievable. The recognition of how one's self impacts the process appeared to be well considered by the process of reflexivity.\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/10-1290
|
https://f1000research.com/articles/10-950/v1
|
21 Sep 21
|
{
"type": "Research Article",
"title": "Risk factors and hematological profile associated with colic in Delman horses in Gresik, Indonesia",
"authors": [
"Muhammad Thohawi Elziyad Purnama",
"Dodit Hendrawan",
"Arya Pradana Wicaksono",
"Faisal Fikri",
"Agus Purnomo",
"Shekhar Chhetri",
"Dodit Hendrawan",
"Arya Pradana Wicaksono",
"Faisal Fikri",
"Agus Purnomo",
"Shekhar Chhetri"
],
"abstract": "Background: Horses are herd animals that have been domesticated in the last century. In several countries, an overview of risk factors and clinical evaluation in horses with colic has not been well‐described. This study aimed to evaluate risk factors and hematological profiles in horses associated with colic in Gresik, East Java, Indonesia. Methods: A cross-sectional study was performed during April - October 2019. A total of 115 horses were diagnosed based on physical examination, clinical symptoms, and rectal examination. A questionnaire was asked to the horse-owners to analyze the risk factors while the clinical examination was performed and blood samples were collected for pre-treatment and 14 days post-treatment. Hematological profile was evaluated from a whole blood sample. Serum cortisol, plasma epinephrine, and norepinephrine concentrations were also evaluated after separating the aliquots. Results: Of the 115 horses, 96 were diagnosed with colic. The horses with colic showed a significant association between cases with gender (p<0.021), breed (p<0.000), wheat bran feeding (p<0.015), concentrate feeding (p<0.003), anthelmintics administration (p<0.000), gastrointestinal parasites (p<0.000), dental diseases (p<0.024), previous exposure to colic (p<0.000), body condition score (p<0.000), and access to water per day (p<0.000). Based on whole blood and serum evaluation, there were ameliorated significantly on the hematological profile (p<0.01), serum cortisol (p<0.05), and plasma epinephrine (p<0.01) at 14 days post-treatment. Conclusion: This study has identified factors associated with colic in Delman horses. The study provides crucial information to investigate cases of colic and to contribute the development of healthcare strategies during treatment and clinical evaluation.",
"keywords": [
"colic",
"Delman horses",
"domesticated animals",
"Gresik",
"hematological profiles",
"risk factors"
],
"content": "Introduction\n\nColic is defined as abdominal pain which is the most common cause of death in horses. Colic is categorized into two types: true colic caused by disorders of the digestive tract, and pseudo-colic due to disorders of organs other than the digestive tract.1 True colic can be constipation colic (colon impaction), spasmodic colic (catarrhal enteralgia), tympanic colic (flatulent colic), and gastric colic (gastric distension) which are acute and implied to decrease horse performance and change habits.2 Pseudo-colic can be caused by the presence of urolithiasis, uterine torsion, hepatitis, nephritis, myositis or tying up disease.3 The severity of colic appears to vary from mild to severe based on its cause and treatment. The most common symptoms of colic are anorexia, sweating, restlessness, looking at the belly, kicking or biting the belly, spinning in the stable, scratching the legs, and rolling over. The appearance of common clinical symptoms usually cannot be distinguished between pseudo-colic and true colic.4\n\nThere is a limited overview of the prevalence and cause of horses associated with colic in respective countries, particularly in areas that use the horse for transportation. Colic in horses was reported as a welfare issue and a crucial concern among horse-owners.5 In previous studies, the incidence of colic in the working horse population was reported to be 30.4% in Ireland,6 36.8% in England,7 83% in Egypt,8 54% in Albania,9 and 20% in Sweden.10 Many horses with colic are associated with hemostatic disorders, both as a primary effect and as a complication of cardiovascular disorders.11 Diagnostic procedures and pathophysiological mechanisms were studied in-depth to investigate coagulation disorders in horses.12\n\nIn addition to identifying the history of the disease and performing a physical examination, evaluation of the hematological profile and blood chemistry of a horse can be done to trace the cause of the disease. The results of the examination can localize the cause of the disease based on the liver and spleen function. This method can evaluate hydration status, disease severity, inflammation, specific organ damage, endotoxemia probability, and determine disease prognosis.13 This study was expected to provide an overview of colic risk factors and hematological profiles in horses with colic to monitor the progress of therapy during colic episodes and the possibility of recurrence.\n\n\nMethods\n\nPhysical examination was performed according to standard operating procedures issued by the Indonesian Horse Veterinarian Association. This study was reported according to the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines 2.0: author checklist.49 All efforts were made to ameliorate any suffering of animals. The owner handles the horse by providing a sense of comfort to prevent stress, while the blood was collected according to standard examinations. Thus, a certificate of ethical clearance was not necessary for this study as the study did not affect normal animal behavior. Meanwhile, a permission letter (No.131/ADG/2019) was approved by Gresik Delman Association and informed consent was received by the horses' owner.\n\nThis study was conducted for seven months (April - October 2019). The sample distribution was collected from Dukun (6°59′54.1′S 112°30′32.2′E) (n = 8), Panceng (6°55′42.0′S 112°27′58.0′E) (n = 21), Ujung Pangkah (6°55′10.2′S 112°32′46.7′E) (n = 19), Sidayu (6°59′33.1′S 112°33′44.6′E) (n = 15), Manyar (7°07′21.2′S 112°36′14.5′E) (n = 8), Kebomas (7°09′59.1′S 112°38′17.5′E) (n = 15), Menganti (7°17′34.9′S 112°35′07.9′E) (n = 8), Kedamean (7°19′20.5′S 112°33′57.6′E) (n = 10), and Driyorejo (7°21′11.1′S 112°37′43.9′E) (n = 11) (Figure 1). The questionnaire was collected based on the owners' reporting. Serum and whole blood were evaluated at Gamma Scientific Biolab, Malang, East Java.\n\nLegends indicated by a red square for areas where the horses were investigated. [Source: https://www.arcgis.com/apps/View/index].\n\nA cross-sectional study was designed to enroll Delman horses in Gresik, East Java, Indonesia. A total of 115 Delman horses at 3-11 years old and 300-400 kg weight were studied. The Delman horse as a riding animal was found in the owners' farm. The diagnosis was performed based on animal history, physical examination, clinical symptoms, and rectal examination. A questionnaire was asked to the owner to analyze the risk factors for colic horses. Questions were grouped into the following sections: age, season influence, gender, breed, wheat bran feeding, feeding on green fodder, concentrate feeding, anthelmintics, gastrointestinal parasites, dental disease, previous exposure to colic, body condition score, water source, access to water per day, musculoskeletal disease and bad vices.14 Horse-owners completed the inquiries with one of the study team while the clinical examination was performed and blood samples were collected. In an attempt to validate owner-reported recurrent colic episodes, owners were asked to describe behavioral alterations and clinical signs that horses demonstrated during the colic episodes.15\n\nColic therapy was performed according to current standard methods in the Indonesian Horse Veterinary Association. Lactated Ringers’ solution (Ringer Lactate, Widatra, Indonesia) was administered as initial treatment via jugular vein in all cases. Concurrently, Flunixin Meglumine (Flumine, Jaapharm, Mano, Singapore) was administered routinely in a dosage of 0.5 mg/kg, q 12 h, for three days.16 The time before therapy (admission) was considered as pre-treatment. The next observation period was performed at 14 days as a post-treatment evaluation.\n\nFor pre-treatment and 14 days post-treatment evaluation, blood from the jugular vein (10 ml) was collected into Vacutainer (BD®, USA) with EDTA for measurement of hematological profile and plain tubes for serum isolation, respectively. All plain tubes allowed to clot for 10-20 minutes then centrifuged in a centrifuge machine (Hettich EBA 200®, GER), at a speed of 4000 rpm for 15 minutes.17 The obtained serum was aspirated using a Pasteur pipette into a microtube and stored at −4°C. Serum cortisol was determined using ELISA method (My-Bio-Source®, San Diego, CA, USA).18 Meanwhile, for total protein, albumin, globulin and calcium were determined spectrophotometrically using Biuret method (Biolabo®, France).19\n\nFor hematological profile, whole blood samples were determined using the clinical chemistry analyzer (Hitachi 902®, Roche Diagnostics, USA). Each blood sample for evaluation of plasma epinephrine and norepinephrine concentrations was centrifuged immediately at 2500 rpm for 10 minutes, and plasma aliquots were analyzed using high performance liquid chromatography.20\n\nAll variables in the questionnaire were transformed into nominal criteria. A Chi-square test was performed to analyze independent data for each criterion associated with colic. The final analysis was done using logistic regression analysis with selected variables depending on p-values. Associations derived from conditional logistic regression were marked by odds ratio (OR) and relative risk (RR). A RR >1 reveals increased risk and a RR <1 reveals decreased risk.\n\nData of hematological and hormone evaluation were expressed as mean ± standard deviation (SD) then analyzed using one-way analysis of variance (ANOVA) followed by post hoc Tukey multiple comparisons test. Values were considered significantly different at p < 0.05. Statistical analysis was performed using SPSS v.25 software (IBM, Armonk, NY, USA).\n\n\nResults\n\nDuring the study period, 115 horses were examined and of these, 96 (83.48%) were diagnosed with colic. The colic diagnosis was based on the following typical clinical signs: abdominal pain, abdominal distention, dehydration, intestinal movement, intestinal sound, sense of appetite, heart rate per minute, profuse sweating, frequent urination, congested mucous membrane, and elevated body temperature (Table 1).\n\nAt the initial examination in the present study, all suspected horses were not classified based on the colic severity. Furthermore, according to the 96 questionnaires from colic horses and 19 questionnaires from normal horses, colic was associated with gender (p < 0.021; OR = 0.317), breed (p < 0.000; OR = n/a), wheat bran feeding (p < 0.015; OR = 0.180), concentrate feeding (p < 0.003; OR = n/a), anthelmintics administration (p < 0.000; OR = n/a), gastrointestinal parasites (p < 0.000; OR = n/a), dental diseases (p < 0.024; OR = n/a), previous exposure to colic (p < 0.000; OR = 32.250), body condition score (p < 0.000; OR = 0.022), and access to water per day (p < 0.000; OR = n/a) (Table 2).\n\nIn addition, based on RR score, an increased risk for colic was found for male horse (RR = 2.021), those administered wheat bran feeding (RR = 1.481), >5 kg of concentrate feeding (RR = 1.500), not performed anthelmintic administration (RR = 4.571), present of gastrointestinal parasites (RR = 4.364), present of dental diseases (RR = 1.280), colic recurrence (RR = 7.579), and poor body condition score (RR = 5.726) (Table 2).\n\nComparative results regarding the hematological profile of the normal and horse with colic during pre and 14 days post-treatment are presented in Table 3. In general, at 14 days post-treatment, the horses with colic improved significantly compared to pre-treatment according to blood parameters [TRBCs (p < 0.001), HB (p < 0.001), PCV (p < 0.001), MCV (p < 0.001), MCH (p < 0.001), MCHC (p < 0.01), neutrophil (p < 0.001), basophil (p < 0.001), monocyte (p < 0.01), and lymphocyte (p < 0.001)], clotting factors [Plt (p < 0.001), MPV (p < 0.001), PDW (p < 0.001), CT (p < 0.001), Prt (p < 0.001), Appt (p < 0.001), and fibrinogen (p < 0.001)], and other biochemical profiles [total protein (p < 0.001), albumin (p < 0.001), globulin (p < 0.001), and calcium (p < 0.001)]. The result was also revealed that all variables at 14 days post-treatment improved gradually similar to the normal group (Table 3). The reference range21 was also provided to add dynamic information on clinical evaluation during treatment of the colic episodes.\n\nAs shown in Figure 2, serum cortisol (p < 0.05) and plasma epinephrine (p < 0.01) concentrations were decreased significantly at 14 days post-treatment compared to pre-treatment. However, plasma norepinephrine showed no significant difference (p > 0.05) at whole colic episodes. These findings indicate amelioration of the degree of sympathetic activation in horses associated with colic at 14 days post-treatment.\n\nValues are expressed in mean ± SD. One-way ANOVA was carried out followed by post hoc Tukey multiple comparisons test. Values are represented statistically when a,b,c, in comparison with normal group; * p < 0.05, ** p < 0.01, *** p < 0.001, in comparison with pre-treatment group.\n\n\nDiscussion\n\nThe current study presents the incidence and risk factors for the recurrence of colic in horses. Colic is still the main concern in horse management worldwide. In this study, the incidence of colic was higher in 71 male horses than 25 female horses (Table 2). The incidence in Sumba horse was higher than other breeds, where 89 cases (92.7%) with colic were Sumba, five cases of Thoroughbred and two cases of mixed breeds (Table 2). Male horses are widely used for traditional transportation. Meanwhile, female horses are only kept in the breeding area and are rarely used as working horses.22 Sumba horses originated from the Sumbawa island and its known for having high movement and mobility. Sumba horses are commonly used as traditional transportation due to their ability to explore and survive in tropical environments.23\n\nThe administration of wheat bran (58 cases) and >5 kg of concentrate feeding (64 cases) can increase the risk of colic especially if it does not appropriate the normal horse feed ratio (Table 2). The procedure for feeding foals and five year old horses was equal. Horses in the growth period require quality raw materials for feeding, including protein with balanced amino acids for muscle development, contributing energy to the metabolic processes. Feed formula ratio consists of 60-70% concentrate.24 Weaning horses are able to consume up to 3.5 kg of concentrate with 14-16% crude protein. The ratio of green fodder and concentrate is 30: 70 based on the dry matter. When a year old, horses need 13.5% crude protein with a green fodder ratio and a 40:60 concentrate of dry matter in the total ratio. Crude protein intake decreases to 11.5% at 18 months with a ratio of green fodder and 55:45 concentrate of dry matter ratio. Meanwhile, at the age of 24 months, crude protein needs reach up to 10% with a ratio of green fodder and 65:35 concentrate based on dry matter ratio.25\n\nIn our study, 75 cases of colic horses without anthelmintic administration and 74 horses with administration were found to have gastrointestinal parasitic infections (Table 2). Worm infections can occur through a single or mixed infection. Different types of infections occur in each animal due to differences in immunity to the worm infection.26 Deworming leads a major role in controlling mixed infections. Horses infected with more than one type of worm may have a weak immune condition. Body endurance can be influenced by various factors such as nutrient intake, enclosure conditions, weather, anthelmintic administration, and the development factor of larval life in grasslands, i.e. climatic conditions, soil type, geographical location, and types of plants. High rainfall can also increase soil moisture. Humid conditions support infective larvae to survive.27\n\nThere were 21 cases of colic horse with dental disease in our sample (Table 2). Special treatment is needed due to the condition of the horses’ teeth, which are not suitable for chewing hard grass. Low lignin grass will be easily digested mechanically to prevent the risk of colic.28 Lack of access to water per day can increase the risk of colic. In this study, horses received water access (per day) once in 25 cases, twice for 60 cases, three times for eight cases and more than three times for three cases (Table 2). Horses must regularly get access to water to prevent colic at least eight liters every 6 hours.29\n\nIn this study, 86 cases of horses had a history of colic, with 81 cases also having poor body scoring conditions (Table 2). Poor body score condition and previous history of colic are correlated with recurrent colic cases. The aspects of the body score are influenced by daily nutrition, horse training, movement intensity, and anthelmintic administration. Horses who get regular dental and nail checks can improve animal behaviour. Horses with a history of colic should receive special treatment after feeding. Mild activity and exercise after feeding can reduce the risk of horse colic.30\n\nCases of colic in horses can be associated as a cause of blood coagulation disorders.31 It is triggered by an increase in blood concentration and a simultaneous decrease in coagulation factors.32 Common symptoms of coagulopathy can be associated in colicky horses with gastrointestinal lesions, ischemia, inflammation, and peritonitis, which also depend on the severity of intravascular coagulation.33 In the current study, the decrease in total platelet and fibrinogen at pre-treatment increased after 14 days post-treatment. In addition, there was an increase in coagulation time, activated partial thromboplastine time and prothrombine time at pre-treatment followed by a decrease after 14 days post-treatment. Thrombocytopenia, hypofibrinogenemia and decreased blood clotting time are reflected in the length of capillary refill time and petechial bleeding. Moreover, if the disorder is followed by inflammation as an activator of platelets which is released as an endogenous mediator.34\n\nCoagulation is disseminated in overlapping stages i.e. initiation, amplification, and propagation.35 The initiation stage is characterized in cells that express tissue factor, which forms a complex with factor VIIa and activates factors IXa and Xa. Factor Xa binds to factor Va on the cell surface and produces a small amount of thrombin. Factor Xa is immediately inhibited so that it cannot move to other cells.36 The amplification stage is characterized after exposure to colic, where platelets are released from the blood vessels, resulting in platelet attachment to the thrombin produced at the initiation stage. Thrombin activates platelets followed by surface changes and the release of partially active factor V. Thrombin also activates cofactors V and VIII, and activates factor XI to factor XIa.37 The propagation step is performed on the surface of activated platelets. At this stage factor IXa binds to VIIIa, followed by an increase in the number of factor IXa as a result of platelet binding to factor XIa. The factor IXa/VIIIa complex activates factor Xa on platelets and immediately binds to factor Va thereby converting prothrombin to thrombin, followed by the thrombin complex converting fibrinogen to fibrin.38 In another study, it has been reported that prolonged activated partial thromboplastine time and prothrombine time are the most frequently observed abnormalities in the coagulation profile of the colicky horse.39\n\nThis study showed an increase in total protein, albumin, and globulin in the pre-treatment period. Several colicky horses with symptoms of dehydration, hemoconcentration, and acute loss of consciousness showed similar results with an increase in total protein.40 In addition, decreased calcium levels are associated with tremor and muscle paralysis during episodes of colic.41 Calcium also plays a role in the coagulation stage, in particular being positively correlated with fibrin activity.42\n\nMeanwhile, serum cortisol and plasma epinephrine levels were detected to be elevated in colic episodes in our study. This activity is predicted to be associated with an increase in plasma lactate concentration, blood pH, heart rate, and hemodynamic disorders.43 The severity of septic shock following lactic acidosis has the potential to induce acute endotoxemia and deteriorating the condition of the horse during episodes of colic. High levels of plasma epinephrine can carry a risk of death.44 In a previous study, horses did not survive if the plasma epinephrine concentration was <4 pg/mL at initial examination, whereas some colicky horses survived at a concentration of 222 pg/mL.45 However, no definitive references have been reported for survivor horses in episodes of colic. The hemostatic response during tissue hypoxia and a decrease in mean arterial pressure are indicated to be the cause of the high plasma epinephrine concentration.46 The increase in serum cortisol concentration during episodes of colic accumulates as a secondary result of increased secretion of the adrenal glands.47 An indication of stress during colic episodes may be the common symptom of high serum cortisol concentrations, as shown in this study. In addition to our identified risk factors, the results of this study revealed improvements in hematological profiles, serum cortisol, and plasma epinephrine. We also emphasized information on the probability of coagulopathy and hemodynamic disorders during a colic episode.\n\n\nConclusion\n\nIn conclusion, the main risk factors for colic in Delman horses in Gresik are gender, breed, wheat bran feeding, concentrate feeding, anthelmintics administration, gastrointestinal parasites, dental diseases, previous exposure to colic, body condition score, and access to water per day. Meanwhile, evidence of improved hematological profile, serum cortisol and plasma epinephrine were observed at 14 days post-treatment for colic. This study may be used to inform future prospective studies investigating colic in working horse populations and to contribute effective preventative measures.\n\n\nData availability\n\nFigshare: Risk factor in horse with colic. https://doi.org/10.6084/m9.figshare.15148851.v1.48\n\nThis project contains the following underlying data:\n\n• Risk factor in horse with colic.xlsx\n\n\nReporting guidelines\n\nFigshare: ARRIVE checklist for ‘Risk factors and hematological profile associated with colic in Delman horses in Gresik, Indonesia’.\n\nhttps://doi.org/10.6084/m9.figshare.16617511.49\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors acknowledge the Faculty of Veterinary Medicine, Universitas Airlangga and PSDKU Banyuwangi for providing fund support to carry out this study. We also thank the horse owners and Gresik Delman Association for the facilities and permission in this study.\n\n\nReferences\n\nScantlebury CE, Archer DC, Proudman CJ, et al.: Recurrent colic in the horse: incidence and risk factors for recurrence in the general practice population. Equine Vet. J. 2011; 43: 81–88. Publisher Full Text\n\nSutton GA, Dahan R, Turner D, et al.: A behaviour-based pain scale for horses with acute colic: scale construction. Vet. J. 2013; 196(3): 394–401. PubMed Abstract | Publisher Full Text\n\nLittle D, Blikslager AT: Factors associated with development of ileal impaction in horses with surgical colic: 78 cases (1986–2000). Equine Vet. J. 2002; 34(5): 464–468. 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Part 2: Calcium, sodium, chloride and phosphate. Equine Vet Educ. 2006; 18(6): 320–325. Publisher Full Text\n\nLee MY, Verni CC, Herbig BA, et al.: Soluble fibrin causes an acquired platelet glycoprotein VI signaling defect: implications for coagulopathy. J. Thromb. Haemost. 2017; 15(12): 2396–2407. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLawson AL, Opie RR, Stevens KB, et al.: Application of an equine composite pain scale and its association with plasma adrenocorticotropic hormone concentrations and serum cortisol concentrations in horses with colic. Equine Vet Educ. 2020; 32: 20–27. Publisher Full Text\n\nSmuts C, Mills J, Myles R, et al.: Lactate dehydrogenase activity in abdominal fluid from horses with colic. J Equine Vet Sci. 2016; 36: 58–62. Publisher Full Text\n\nSellon DC, Roberts MC, Blikslager AT, et al.: Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J. Vet. Intern. Med. 2004; 18(4): 555–563. PubMed Abstract | Publisher Full Text\n\nKohno R, Detloff BL, Chen LY, et al.: Greater early epinephrine rise with head-up posture: a marker of increased syncope susceptibility in vasovagal fainters. J. Cardiovasc. Electrophysiol. 2019; 30(3): 289–296. PubMed Abstract | Publisher Full Text | Free Full Text\n\nContreras-Aguilar MD, Escribano D, Martín-Cuervo M, et al.: Salivary alpha-amylase activity and cortisol in horses with acute abdominal disease: a pilot study. BMC Vet. Res. 2018; 14(1): 1–7.\n\nPurnama MTE, Hendrawan D, Wicaksono AP, et al.: Risk factor in horse with colic. figshare. Dataset. 2021. Publisher Full Text\n\nPurnama MTE, Hendrawan D, Wicaksono AP, et al.: ARRIVE report checklist. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "94978",
"date": "14 Oct 2021",
"name": "Hamny Sofyan",
"expertise": [
"Reviewer Expertise Animal Anatomy and Physiology",
"immunohistochemistry"
],
"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 comments: This research analyzed the risk factors for colic in Delman horses in Gresik, Indonesia and showed the success of the treatment based on hematological and biochemical profile and also catecholamine hormone levels. The result of this study can be used to decrease the incidence of colic in Delman horses in Indonesia.\nSpecific comments:\nTitle:\nSuggestion for title: Risk factors, hematological and biochemical profile associated with colic in Delman horses in Gresik, Indonesia\nIntroduction Author should pay more attention in this section. Author needs to highlight the researchable problem with colic in Delman horses, especially in Indonesia. Add the information about incidence rate of colic is in horses in Indonesia (if data is available).\nMethods I think this study requires ethical clearance because there was a blood collection process and treatment was carried out in Delman horses with colic. Does your unit have ethics related to routine procedures performed on animals? If there is, I don't think ethical clearance is needed anymore.\nResults\nI found discussion statement in the result section, please revised it.\n\nSuggestion: the title of Table 3: Hematology profile and blood biochemistry at pre and 14 days post-treatment in Delman horses with colic.\nDiscussion\nI think the discussion should be focus on the risk factors that significantly influence the occurrence of colic in Delman horses according to the results of this study and then compare with previous study.\n\nIn this section, the relationship between hematology and chemical components of blood with the incidence of colic in Delman horse have not been clearly.\n\nWhy are working horse not included in the variables of risk factors?\nConclusion\n“Meanwhile, evidence of improved hematological profile, serum cortisol and plasma epinephrine were observed at 14 days post-treatment for colic”. What is the meaning of this statement? Does this mean that the colic treatment has been suitable?\n\nPlease, add the future improvements based on the research results in this 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?\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": "7622",
"date": "10 Jan 2022",
"name": "Muhammad Thohawi Elziyad Purnama",
"role": "Author Response",
"response": "Dear Dr. Hamny I would like to thank you for your kind review of our manuscript. We have improved the title and Table 3 heading according to your suggestion. Regarding the introduction section, we only found a colic report based on a repository and not yet published properly. We have attached the ethical review along with the document (ARRIVE) guidelines 2.0: author checklist. We have also revised the results and discussion sections according to the findings of the investigated risk factors and compared them with previous study reports. As emphasized in the conclusion section, this study showed improvement in the condition of horses after treatment. Further studies need to examine the association of working horse risk with colic which is a limitation in this study. All the best wishes. Thank you."
}
]
},
{
"id": "94979",
"date": "03 Dec 2021",
"name": "Muhammad Fiaz Qamar",
"expertise": [
"Reviewer Expertise Molecular and diagnostic 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\nI have reviewed the manuscript and found minor gaps in the manuscript. The manuscript is well-written and clear to understand. A small number of typos and grammatical errors are present in the manuscript.\nManuscript contains risk factors data associated with Colic in horses, some other risk factors can be added or addressed.\nThe introduction section only describes the colic and its prevalence, the introduction should also contain the risk factors already reported and hematological alterations reported by researchers. Similarly, the prevalence parameter is missing in the methods section.\nThe discussion section needs some improvements regarding objective and protein.\nThe conclusion section can be improved by adding missing links for future studies.\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": "7623",
"date": "10 Jan 2022",
"name": "Muhammad Thohawi Elziyad Purnama",
"role": "Author Response",
"response": "Dear Prof. Fiaz. I would like to thank you for your kind review of our manuscript. Regarding your judgment on our manuscript, we have added to the risk factor information gap in previous studies and the association with colic-relevant disease. We have added additional information on total protein as part of the discussion because it relates to the duration of the examination during colic. In the conclusion section, we have emphasized further research and the most important risk factors to be evaluated during the colic period. All the best wishes. Thank you."
}
]
}
] | 1
|
https://f1000research.com/articles/10-950
|
https://f1000research.com/articles/11-21/v1
|
10 Jan 22
|
{
"type": "Research Article",
"title": "Setting Limits on Screen Time for Children (6-to-12 Years): The Integral Role of Parents and Educators.",
"authors": [
"Megan Hastie"
],
"abstract": "This paper investigates the effects of screen time on child development and cognition and the setting of ‘safe’ screen time limits for young children, specifically children aged 6-to-12 years. Guidelines on screen time vary across constituencies, and the debate around screen time is contentious with many questions yet to be answered. A review of literature was undertaken to compare current screen time recommendations against the evidence from Neuroscience, Psychiatry, Psychology and Pediatrics that quantify screen time effects on the children's brain development. Based on this comparison, conclusions are made that can guide education policies around ‘remote learning’ and ‘home schooling’ to align them with the available research on the effects of screen time on children and inform a re-evaluation of the role of parents and educators in the setting of ‘safe’ limits on screen time.",
"keywords": [
"screen time",
"digital media",
"children",
"adolescents",
"brain development",
"cognition",
"neuroimaging",
"cerebral cortex",
"ADHD",
"Internet addiction",
"COVID-19",
"remote and distance learning"
],
"content": "Introduction\n\nThe debate around screen time for children is contentious. This paper investigates the effects of screen time on child development and cognition and the setting of ‘safe’ screen time limits for young children. The focus in this paper is the cohort of children aged 6-to-12 years, that is, children enrolled in primary (elementary) and early secondary school in Australia (ACARA, 2019). At the centre of this investigation of screen time is the brain development and cognition of children. While it is acknowledged that genetics and everyday experiences and relationships combine to shape early brain development, it is the timing and quality of early experiences, including screen time, that shape the architecture of the brain (Harvard University, 2004, p.2; 2008, p.1).\n\nAccordingly, evidence will be drawn from Neuroscience, Psychiatry, Psychology and Pediatrics to quantify the effects of screen time on the brain development of children in the years between 6 and 12 years, a critical period or ‘prime time’ for brain development (AEDC, 2019, p.1), and an ‘often-overlooked period of childhood’ (Hagan & Shaw, 2020, p.1). Given the importance of brain development and cognition in early childhood, and the growing interest in the ‘brain and body-based implications of technology use in children and adults’ (Gottschalk, 2019, p.6), longitudinal studies are included from studies of children who are both younger and older, that is, from before and after the primary (elementary) school years.\n\nGrowing up in a ‘digital’ world means children have unprecedented access to devices with screens and spend more time looking at screens than any previous generation. Consequently, children have ‘the most to gain and are most at risk from digital technologies’ (The Lancet Editorial, 2018, p.1; Straker et al., 2018, p.301). The debate around screen time, therefore, and the setting of ‘safe’ limits for children has never been more urgent. The word ‘safe’ refers to practices that ‘prioritise the safety and wellbeing of children’ and have the best interests of the child as a primary consideration (Australian Government, National Office for Child Safety, 2020, p.5). The term ‘screen time’ is defined as the ‘time spent viewing content displayed and projected from active and passive screen-media that present visual information on two-dimensional displays’ (Suggate & Martzog, 2020, p.2), using devices that include television screens, computer monitors, and mobile handheld devices such as smartphones and tablets to check email, listen to music, watch TV, and play video games (National Institute of Health, Educational Campaigns, 2013, p.1).\n\nThe debate around screen time is not new. Prior to the advent of computers and screen-based digital devices (Leiner et al., 1997, p.2), concerns about the negative influences of television on the health and behaviour of children were raised by parents and health professionals (Jordan et al., 2006, p1; Bybee et al., 1982, p.4), that were associated with the increased prevalence of childhood obesity (Cui, 2011, p.1-8; Gortmaker et al., 1996, p.1), and ‘inappropriate, risky or illegal behaviours’ (Bar-on, 2010, p.1; Stranger, 1997 p.8; Cantor et al., 1996, p.4). Described in terms of ‘video deficit’, television ‘consistently failed to teach as much as live interaction’, resulting in lower performance on ‘simple imitation tasks, language learning, and emotional learning’ for children aged 2 years and younger (Anderson et al., 2005, p.1), with ‘imprecise long-term educational outcomes’ for children under 6 years (Kearney & Levine, 2019, p.318), and ‘poor longer-term educational achievement’ (Hancox et al., 2005, p.614).\n\nIn contemporary society, the increased role of electronic media in daily life has created ‘a digital minefield’ for children, parents and educators. Described as ‘the biggest educational experiment in history’ (Sahlburg, Gonski Institute for Education, 2020, p.1), screen time has been ‘normalised’. Globally, the COVID-19 pandemic (the pandemic), forced millions of children and families into mandatory periods of quarantine and isolation, estimated by UNESCO at over 1.5 billion students, or 87% of the world’s student population, across 165 countries (UNESCO, 2020, p.1). Where digital technologies could be mobilised, home and school became one-and-the-same, with screen-based devices used for both education and entertainment. Children moved seamlessly between online and offline environments, with daily communication and screen time ‘intertwined’ (Reid et al., 2016, p.1). Predictably, children spent more time on-screen, raising questions about the effects of screen time on learning, the content viewed (Sheen et al., 2020, p.1), and the role of parents and educators (Australian Broadcasting Corporation, 2020, p.1; Graham & Sahlberg, 2020, p.11). Parents, it was suggested, needed to be educated on the ‘harmful effects of early screen use’, through training in ‘adaptive parenting skills’, and strategies for intervention, with resources providing ‘alternative activities’ to enhance the mental, social, and emotional development of children (Wong et al., 2021, p.1; Trinh, 2019, p.77; Lauricella et al., 2015, p.1). However, in Australia, the mental health, wellbeing and education of children and adolescents, worsened during the pandemic (Australian Government, Office of the eSafety Commissioner, Open Letter to Australia’s Parents and Carers, 2021a, p.1; Murdoch Children’s Research Institute, 2021, p.1), highlighting the importance of children returning to classrooms and physical-face-to-face learning with their teachers (Murdoch Children’s Research Centre, 2020, p.1). Thus, many questions around screen time are yet to be answered. How much screen time is adequate, or not enough, or too much for young children? What are the effects of screen time on child development? Not surprisingly, the debate around screen time remains contentious, especially since the guidelines vary across constituencies.\n\nThe potential to promote learning using Information Communication Technology (ICT) and Technology Enhanced Learning (TEL) is already established (Graham & Sahlberg, 2021, pp.39-41; Hooft Graafland, 2018, p.45; The Lancet Editorial, 2018, p.1; AAP, 2016a, p.1). Value has been demonstrated in the use of the ‘Holistic Blended Learning Model’ (Chen et al., 2008, pp.252-253), that combines Physical Synchronous, Physical Asynchronous, Cyber Synchronous and Cyber Asynchronous modalities (Hastie, Hung, Chen, & Kinshuk, 2010). Research findings have documented ‘best practice’ in instructional design (Gagné et al., 2005, pp.1-17), in the Cyber Synchronous classroom (Hastie & Smith, 2017; Hastie, Chen, & Smith, 2011a; Hastie, Chen, & Kuo, 2007), and the management of cognitive load (Sweller, 1988, pp.257-285) to optimize student learning in screen-based learning environments (Hastie, Chen & Smith, 2012). Applications of these strategies are reported in studies of the teaching of Science, Technology, Engineering & Mathematics (STEM) and educational robotics via the Internet (Hastie, 2018; Hastie, 2016), and in professional development programs for teachers and medical educators working in e-learning paradigms (Hastie, Dornan, Chen, Smith & Elston, 2013; Hastie, Chen & Smith, 2011b; Marzano et al., 1997, pp.1-12; Hastie & Palmer, 1997). Irrespective of such potential benefits, the effects of screen-time on young children remain inconclusive. This paper then is a contribution to that discussion of education policy and pedagogy.\n\n\nDiscussion/Literature review\n\nThe literature is analysed from two perspectives. First, the current screen time recommendations for 6-to-12-year-old children are established. Second, to determine the effects of screen time on the brain development and cognition of young children, research findings from Neuroscience, Psychiatry, Psychology and Paediatrics are presented. Finally, a summary of this literature, based on a comparison of the two perspectives, is made to identify best practices. I now turn to these tasks.\n\nThe guidelines for screen time have changed over time and have been set largely by the American Academy of Pediatrics (AAP). In 2013, the AAP made the following recommendations on the use of electronic media, as listed in Table 1:\n\nThen in 2016, the AAP released revised guidelines that acknowledged the ‘multifactorial effects of media use’ on children. Recommendations included the need for ‘mindful selection, curation, and co-viewing of content’ by parents, and a ‘personalized media use plan’ that attended to the ‘age, health, temperament, and developmental stage’ of each child. Also acknowledged were the significant challenges faced by parents in setting limits on screen time and in limiting the media consumed by children, especially when children owned their own digital devices (AAP, 2016b, p.1). Even so, parents of school-aged children were advised to ‘carve out’ media limits each day to include 8-10 hours of sleep, 2 hours of screen time, 1 hour of physical activity, and 0 sugary drinks (Swartz, 2016, p.1). Such limits were intended to ‘reduce the risks of obesity, lost sleep, and impaired school performance’, while allowing children to ‘connect online with friends and family and learn about the broader world’. The goal was to keep children off their devices, that is ‘unplugged’, for at least 2 hours per day (Christakis, Medscape Medical News, 2016, p.1).\n\nIt was claimed, however, that the AAP (2016b) guidelines, were based on ‘out-of-date research’ conducted before digital devices had become part of everyday life (University of Oxford, 2017, p.1). The time-lapse between the original research and publication made the recommendations ‘difficult to justify and implement’. A re-evaluation of the guidelines was suggested to determine whether they were good for the mental health and wellbeing of young children. Thus, the differing opinions of health and education authorities, as revealed here, created ‘policy and practice dilemmas’ and ‘conflicting guidelines’, on screen time for young children (Straker et al., 2018, p.300).\n\nImportantly, ‘no consistent evidence of health benefits or safe thresholds’ for screen time for children and young people could be identified, with no evidence supporting ‘differential thresholds’ for younger children or adolescents (Stiglic & Viner, 2018, p.14). Very limited evidence was found for a threshold to guide policy on screen time exposure. Nonetheless, evidence of ‘health harms’ across a ‘broad range of domains of physical and mental health, including adiposity, unhealthy diet, depressive symptoms, and quality of life’, broadly supported ‘policy action’ to ‘limit screen use by children and young people’. Suggestions included the setting of limits on screen time for children and young people, and consideration of the impact of the content or contexts of digital screen use, specifically the use of mobile digital devices, on their health and well-being. Organizations such as the AAP were encouraged to consider ‘extending recommendations’ for specific limits on screen time to ‘preteens and teens’ (Twenge & Campbell, 2018, p.280), along with the provision of a diverse menu of online and offline experiences with opportunities for children to let their minds wander and experience boredom, the space in which creativity and imagination happen (Harvard Medical School, 2019, p.1).\n\nA more ‘nuanced’ stance on screen time was proposed in response to the increasingly pervasive and ubiquitous role of media in the lives of children (American Academy of Child & Adolescent Psychiatry, 2020, p.1080). For children aged 6-and-older, the AACAP encouraged the development of ‘healthy’ habits with a ‘consistent’ limit on activities that involved screens, including greater scrutiny of children’s access to screens (especially portable devices), the content accessed, who children are with and how they interact when looking at screens (American Psychological Association, 2020, p.42). Australian parents were advised there was ‘no magic figure’ that could be used to determine how much screen time was safe for young children. The ‘right’ amount of screen time depended on the age and maturity of the child, the kind of content the child was consuming, their learning needs and family routine (Australian Government, Office of the eSafety Commissioner, 2021b, p.1), and the cost of time spent on screen to health, wellbeing and opportunities to live a balanced life (Graham & Sahlberg, 2021, p.5; Longitudinal Study of Australian Children, 2016, p.99). Consequently, no maximum limit on screen time was set for Australian children. However, moderation of screen-use was recommended to promote cognitive development in children (Walsh et al., 2020, p.4), along with the need for the general discussion around screen time to ‘go beyond simply limiting screen time’, to promoting the use of screens in ways that are ‘positive’ for the brain (University of Washington, 2021, p.1).\n\nWhile the current guidelines (AAP, 2016b; ACAP, 2020) provide criteria for the use of media and exposure to screen-based devices, it is necessary to set them against what are known to be the effects of screen time on young children, and the developmental trajectory of children. To that end, the literature from medical science, specifically evidence-based research from Neuroscience, Psychiatry, Psychology and Paediatrics, is investigated.\n\nNeuroimaging technologies, specifically ‘Magnetic Resonance Imaging’ (MRI) and ‘functional MRI’ (fMRI), have provided evidence that correlate screen time with ‘structural changes’ in the brains of children aged 0-18 years (Raschle et al., 2012, p.2). ‘Lower microstructural integrity’ of brain white matter tracts were identified in children, aged 3-to-5 years, who used more than the screen time recommended by the AAP (2016b), that is, more than 1 hour per day without parental interaction (Hutton et al., 2019, p.8). Average screen time for these children was slightly more than 2 hours per day but ranged from 1 hour to slightly more than 5 hours per day. Tracts that supported ‘language and emergent literacy skills, cognition, and executive functions’, were ‘more disorganized and underdeveloped’. Screen time, it was concluded, was ‘too passive’ for brain development, and ‘displaced’ other experiences that could have ‘helped children reinforce brain networks more strongly’ (Hutton, LaMotte, CNN News Health, 2019, p.1). Premature ‘thinning’ of the cerebral cortex, that is, cell loss or ‘atrophy’ in the outermost layer of the brain was identified through neuroimaging in children aged 9-to-10 years who used screen-based media for more than 7 hours per day (World Economic Forum, 2018, p.1). Similarly, ‘structural deficits’ in the cortex, identified through neuroimaging, were attributed to excessive online gaming in Chinese adolescents and young adults. ‘Decreased left orbitofrontal grey matter volume’ was found after 6 weeks of daily online gaming in both ‘excessive gamers’ and ‘gaming-naïve' subjects (Zhou et al., 2017, p.100-109;). New rules were announced in China in 2021 to ‘combat gaming addiction’ with online video games limited to 3 hours per week for children under-18 years (Reuters, 2021, p.1; AppInChina, 2007, p.1; China Daily, 2006, p.1).\n\nCorrespondingly, ‘reductions in cortical thickness’, across prefrontal, parietal, and temporal regions of the brain that was attributed to ‘social deprivation in early life’, was associated with attention deficit hyperactivity disorder (ADHD) approximately four or five times more often than other children (McLaughlin et al., 2014, p.8). Significant ‘cortical thinning’ was also found in children with ‘Fetal Alcohol Syndrome Disorder’ (FASD) in large areas of the ‘bilateral middle frontal lobe, pre- and post- central areas, lateral and inferior temporal and occipital lobes of the brain’ (Zhou et al., 2011, p.1). Excessive or long-lasting stress, known as ‘toxic stress’, that included ‘physical or sexual abuse, neglect or lack of affection, parental mental illness, family violence, poverty, and lack of adequate housing’, had a negative impact on brain development, especially in the early years (Harvard University, 2021, p.1). While thinning of previously thicker areas of the brain is generally associated with aging, ‘Alzheimer’s disease’ (AD) and ‘progressive brain disorganization’ (Roe et al., 2021, pp.5-6), it is not observed in otherwise healthy children.\n\nResearch from animal models (Waxmonsky, 2019, p.1) found frequent exposure to rapidly changing audio and visual bombardment, the hallmarks of many television shows and video games, had prevented brain nerve tracks from developing as intended. These findings, when extrapolated to brain development in children, pointed to ‘what children were not doing’, and ‘what was not happening in their brains’, because they were ‘staring at screens’. It was concluded that there was ‘nothing inherently beneficial about viewing screens’, rather, ‘a matter of how much risk’ screens posed (Waxmonsky, 2019, p.1-2).\n\nIn Australian research, the synchronisation of social and emotional networks in the brain was correlated with active human engagement, known as ‘interpersonal neural synchronisation’ or neural coupling (Kerr, 2019, p.14). Physical face-to-face interactions ‘activate different parts of the brain’ that are not activated during virtual meetings (Hasson et al., 2012, pp.6-8). Intensive physical face-to-face interactions, when used within the Auditory-Verbal Therapy (A-VT) approach to teach Australian children (0-18 years) with hearing loss to listen and speak, built and strengthened neural pathways in the auditory area of the brain, in areas where cognitive growth and language development is promoted (Dornan et al., 2011, 2010, 2009, 2009, 2008, 2007).\n\nNotably, changes in the anatomical and physiological development of the brain, particularly the connection between the prefrontal cortex and executive function, were aligned with Piagetian child development theory (Bolton & Hattie, 2017, p.22). It was concluded, therefore, that the first years of life needed to be focused on human interactions, specifically ‘healthy and stimulating experiences’, to ‘build brain architecture’ that can operate at its ‘full genetic potential’ (Harvard University, 2008, p.2).\n\nHigher daily screen time across all screen types was correlated with ‘lower cognition’ in children aged 9-to-10 years, with those in the ‘high’ (7.2 hours per day) and ‘middle’ (2.9 hours per day) screen time groups rated ‘lower in cognition’ when compared to children in the ‘low’ (1.2 hours per day) screen time group (Walsh et al., 2020, p.4). Early data from the NIH 2018 study indicated ‘lower scores in thinking and language tests’ for children whose screen time was ‘more than 2 hours per day’ (CBS News, 2018, p.1). ‘Heavy television use’ by Australian children was predictive of a ‘loss of reading of four months relative to peers two years later’, while ‘heavy computer use’ predicted a similar loss in numeracy two years based on a comparison of academic results from NAPLAN, the National Assessment Program Literacy and Numeracy (Mundy et al., 2020, p.11).\n\nConversely, ‘superior global cognition’ was identified in Canadian children aged 8-to-11 years who ‘adhered to recommendations of physical activity of 1 hour per day, recreational screen time of 2 hours or less per day, and sleep of 9-11 hours duration per night’, while the ‘limiting of recreational screen time’ and the ‘encouragement of healthy sleep’ was correlated with ‘improved cognition’ (Walsh et al., 2018, p.6; Rodriguez-Ayllon et al., 2020, p.5). Increased screen time, however, was correlated with ‘increased problem behaviours’ in children aged 9-to-10 years, whereas ‘sleep of longer duration’ was associated with ‘reduced problem behaviours’ (Guerrero et al., 2019, pp.3-9; Fakhouri et al., 2013, pp.227-228).\n\nThe ‘digital distractions and supernormal capacities for cognitive offloading’ offered during screen time, created a ‘non-ideal environment’ for the ‘refinement of higher cognitive functions during critical periods of brain development’ in children and adolescents (Firth et al., 2019, pp.126-127). ‘Complex and multi-method based visual stimuli’ on screens was associated with ‘overload on working memory’, ‘divided attention’ and ‘impaired recall’. The combination of ‘audio-visual graphics, text, and animations’ impeded the ability to ‘register, process, and remember information with accuracy’. Consequently, cognitive overload impacted the ‘quality of comprehension, prioritization, and deep-level processing of incoming information’. Short-term memory, in turn, could not be consolidated into long-term memory, and resulted in ‘poor processing and understanding of what was taught or said’ (Jha & Arora, 2020, p.1). It was argued ‘the screen should be the tool, not the teacher’ (Roseberry Lytle, University of Washington, 2015, p.1).\n\nScreen time was correlated with ‘adverse physiological and psychological effects’ in children and adolescents, aged 0-to-18 years (Lissak, 2018, p.149). Physiological effects attributed to excessive screen time included ‘poor sleep’ and risk factors for ‘cardiovascular diseases (high blood pressure, low HDL cholesterol, obesity)’, ‘poor stress regulation (high sympathetic arousal and cortisol dysregulation)’, ‘Insulin resistance’, ‘impaired vision’ and ‘reduced bone density’ (Lissak, 2018, pp.149-157; Dahlgren, 2021, pp.2-5). Excessive screen time is defined as ‘sedentary time spent on screen, such as watching television, playing video games, or using the computer for more than 2 hours per day’ (de Lucena et al., 2015, p.407) that ‘comes at the expense of other healthy activities’ (Dahlgren, 2021, p.1). Significantly, in 2018 the World Health Organization (WHO) included gaming disorder in the 11th International Classification of Diseases (WHO, 2018, p.1).\n\nPsychological effects, specifically ‘developmental delay’, were associated with screen time in children aged 11-to-13 years when ‘screen versus non-screen interactions’ during early childhood were compared with behavioural problems in early adolescence (Wong et al., 2021, pp.7-11). The ‘duration’ of exposure to screens by children and the ‘frequency’ of non-screen parent-child activities correlated with ‘externalizing problems’ (rule-breaking behaviours, delinquency and aggression) and ‘internalizing problems’ (emotional symptoms, anxiety and depression) in early adolescence. Fewer externalizing problems were observed when young adolescents spent more time on ‘non-screen parent-child activities’, and less time on ‘child-alone’ video game activities. The overall ‘length’ of screen time, along with ‘violent’, ‘fast-paced’ content and ‘repetitive attentional shifts between multiple tasks’, was found to activate dopamine and reward pathways associated with ‘ADHD-related behaviours’, including ‘inattention’, ‘impulsivity’, ‘sleep problems’, and ‘impaired executive functioning’. Extensive screen time and use of technology were correlated with ‘heightened attention-deficit symptoms’, ‘impaired emotional and social intelligence’, ‘technology addiction’, ‘social isolation’, ‘impaired brain development’, and ‘disrupted sleep’, while ‘background media’ had a negative impact on ‘cognitive load’ and ‘attentional capacity’ (Lissak, 2018, p.149-157).\n\nConstant use of technology offered ‘fewer opportunities to interact offline’ and meant ‘the brain could not reset to its default, or resting, mode’ (Small et al., 2020, p.179-187; Kerr, 2019, p.12). ‘Symptoms of ADHD’ were identified in children and adolescents aged 15-and-16 years after 6 weeks of digital media use, although no symptoms of ADHD were identified in baseline data (Ra et al., 2018, p.258-261). A significant association, therefore, was established between more frequent digital media use and ADHD symptoms. Importantly, it was found that ‘screen time induced ADHD-related behaviour’ could be ‘inaccurately diagnosed’ as ADHD, while reduced screen time was effective in decreasing ADHD-related behaviour (Lissak, 2018, p.149). Additionally, the association between screen time and ADHD, was identified in people at any age, with moderate or severe depression and obesity found in adults who spent more than 4 hours per day watching TV and using computers, outside work or school, with females at higher risk (Madhav et al., 2017, p.67-71; Teychenne et al., 2010, p.246-254).\n\nA summary of the effects of screen time on the brain development and cognition of young children and adolescents, along with associated health consequences, is provided in Table 2:\n\n\n\n- poor sleep\n\n- ADHD related behaviours\n\n- risk factors for cardiovascular diseases (high blood pressure, obesity, low HDL cholesterol)\n\n- poor stress regulation (high sympathetic arousal and cortisol dysregulation)\n\n- Insulin resistance\n\n- impaired vision\n\n- reduced bone density\n\n\n\n- Lissak, 2018\n\n\n\n- lower microstructural integrity of brain white matter tracts\n\n- disorganized and underdeveloped tracts in areas that support language and emergent literacy skills, cognition, and executive functions\n\n\n\n- Hutton et al., 2019\n\n\n\n- developmental delay in children\n\n- behavioural problems in early adolescence\n\n\n\n- Wong et al., 2021\n\n\n\n- thinning of the cerebral cortex, cell loss or ‘atrophy’, in the outermost layer of the brain\n\n- lower scores on language\n\n- lower scores on thinking tests\n\n\n\n- World Economic Forum, 2018\n\n\n\n- decreased left orbitofrontal grey matter volume after six weeks of daily Internet gaming\n\n\n\n- Zhou et al., 2017\n\n\n\n- heightened symptoms of ADHD\n\n- impaired emotional and social intelligence\n\n- technology addiction\n\n- social isolation\n\n- impaired brain development\n\n- disrupted sleep\n\n\n\n- Small et al., 2020\n\nConclusions are now presented that are based on a comparison of the science and practice. Expressly, the findings from Neuroscience, Psychiatry, Psychology and Paediatrics on the quantified effects of screen time on the brain development and cognition of children are compared with the current screen time guidelines (AAP, 2016b) for children aged 6-to-12 years.\n\n\nConclusions\n\nFirst, while genetics and everyday experiences and relationships combine to shape early brain development, it is the timing and quality of early experiences, such as screen time, that combine to shape the architecture of the brain. Environmental factors, particularly physical face-to-face interactions, play a critical role in early brain development that extends across the life span. However, screen time is correlated with adverse physiological and psychological effects in children and adolescents, aged 0-to-18 years. Much of what happens on screen, during Cyber Synchronous and Cyber Asynchronous interactions, provides ‘impoverished’ stimulation to the developing brain when compared to reality. Equated with ‘video deficit’, screen time is too passive for early brain development because it replaces other experiences, specifically physical face-to-face interactions and small motor activity, that reinforce and strengthen brain networks. Importantly, greater white matter microstructure in children is associated with higher levels of physical activity, particularly outdoor play and sport participation.\n\nSecond, changes in brain structure in children, specifically thinning of the cerebral cortex as quantified through neuroimaging, were directly correlated with screen time. For children aged 3-to-5 years, screen time that exceeded the AAP guidelines (2016) of more than 1 hour per day without parental interaction, was associated with lower microstructural integrity in brain white matter tracts, in those areas of the brain that support language, emergent literacy skills, and cognition. For children aged 9-to-10 years, more than 7 hours of screen time per day was correlated with a thinning of the cerebral cortex, while more than 2 hours per day was associated with lower scores on language and thinking skills. For children aged 11-to-13 years, screen activities in early childhood activities were associated with behavioural problems in early adolescence.\n\nExtensive screen time and extensive use of technology by children and adolescents were correlated with heightened attention-deficit symptoms, impaired emotional and social intelligence, technology addiction, social isolation, impaired brain development, and disrupted sleep. Symptoms of ADHD were identified in both excessive gamers and gaming-naive subjects after just 6 weeks. Changes in brain morphology attributed to screen time were associated with lower general intellectual functioning (IQ), developmental delay and behavioural problems that extend from childhood across the life span. The evidence, therefore, confirms screen time, from as little as 1 hour per day, can have detrimental effects on the brain development and cognition of young children. Importantly, cortical thinning of the brain is not found in otherwise healthy children, however, it is associated with FASD, social deprivation in early life, aging and Alzheimer’s disease (AD) and progressive brain disorganization in later life. Ergo, the structural changes to the brains of young children attributed to screen time, match the descriptors for toxic brain stress and, as such, constitute physical abuse.\n\nThird, the COVID-19 pandemic heightened issues around screen time, with millions of children globally making the ‘switch’ from physical face-to-face classrooms to ‘remote’ learning from home. Physical face-to-face interactions were replaced by cyber face-to-face, where it was possible to mobilise digital technologies, creating an unprecedented reliance on Information Communication Technologies and Technology Enhanced Learning. Consequently, the extra hours that students spent online for lessons, when added to their recreational screen activities, equated to significantly more screen time overall, at levels that were most likely excessive. In addition, the mental health, wellbeing and education of children and adolescents worsened during the pandemic due to protracted lockdowns and school closures. Further, the increased risks of moderate or severe depression in adults, especially females, due to increased screen time during the pandemic, raises important questions around the health of parents and educators and associated impacts on their role in ‘remote’ learning and teaching.\n\nFourth, the current guidelines for screen time, released by the AAP (2016b), and endorsed by ACAP in 2020, recommend children should be ‘unplugged’ and have no media use for at least 2 hours per day, in contrast to the 2013 recommendations of more adult-regulated and scrutinized media use for children aged 5-18 years. While the current screen time recommendations (AAP, 2016b) are more nuanced, they create confusion due to their reliance on personalized media use plans that attend to the age, health, temperament, and developmental stage of each child. Nonetheless, based on the 2016 guidelines, it could be estimated that, apart from daily physical activity (1 hour minimum), adequate sleep (8 to 12 hours, depending on age), quality family time and time away from media (2-4 hours), school-aged children, including children aged 6-to-12, could be on-screen for 7-13 hours per day, or possibly longer, at levels deemed excessive and which predispose them to Internet addiction.\n\nFifth, no consistent evidence was found of health benefits from screen time. Thus, the research comprehensively supports policy action to limit screen use by children and adolescents, with specific limits on screen time for preteens and teens. Essentially, action is needed to limit sedentary screen time, related to television, video games, and computers, to less than 2 hours per day, to ensure other healthy activities, specifically physical activity, are not displaced. While parents and educators are expected to manage screen time and help children develop the skills and habits needed to grow up in a digital world, this expectation of shared responsibility for digital education with its associated reliance on the use of sophisticated technological devices and resources is, by definition, a contributor to educational inequality.\n\nGiven these conclusions, education policies around ‘remote learning’ and ‘home schooling’, require a review to align them with the available research on the effects of screen time on the brain development and cognition of children aged 6-to-12 years, but more broadly from birth-to-18 years, along with a re-evaluation of the role of parents and educators in the setting of limits on screen time.\n\nFinally, having established wide variance between the science on screen time and current practice, the question is how do we close the gap?\n\n\nDisclaimer\n\nThe findings and conclusions in this paper are those of the author.\n\n\nData availability\n\nNo data are associated with this article.",
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}
|
[
{
"id": "122393",
"date": "10 Feb 2022",
"name": "Antje Hebestreit",
"expertise": [
"Reviewer Expertise Child and adolescent health",
"epidemiology",
"health behaviour"
],
"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\nTitle: Setting Limits on Screen Time for Children (6-to-12 years): The Integral Role of Parents and Educators.\nThank you for the opportunity to review this manuscript (MS). The present review summarizes and discusses the literature examining the different screen time behaviours related to changes in children's brain development and cognition. The author further reflects the current and past screen time recommendations. I have below listed a number of suggestions for the author to consider.\nMajor recommendations:\nGeneral:\n\nI think the role of parents and educators needs to be elaborated a lot more throughout the MS. It is promised in the title, but the MS mainly discusses developmental differences in youth related to screen time. Also, this review is an opportunity to discuss the role of paediatricians as the most reliable health source among both children and adolescents and parents themselves.\n\nThe methods section is completely missing. How was the search of articles conducted? Which databases were searched? Based on which criteria were the articles selected (setting, healthy or diseased children etc.)?\n\nThe single sections of the manuscript do not really differ in content, but show large information overlap between introduction, discussion and conclusion. Please structure the sections better to set the stage and motivate the review (Intro), discuss the results more in depth (Discussion) and summarize main findings that close current research gaps (Conclusion). Also, in the conclusion the argumentation was not clear.\n\nTitle:\nThe title indicates that the paper discusses the integral role of parents and educators in setting safe limits of screen time for children. This was not elaborated enough in the text.\nAbstract:\n“This paper investigates the effects of screen time on child development and cognition and the setting of ‘safe’ screen time limits for young children, specifically children aged 6-to-12 years.”\nThis sentence implies that the article is an original quantitative research article and not a review article. Hence, I suggest to rephrase and make clear that this paper is a review, which aims to synthesize and discuss the current literature investigating the effects of screen time on children’s brain development and cognition (still the role of parents and educators is not really elaborated in the MS, as promised in the title). I also would suggest to include the main findings in the abstract, also the methods and outcomes are missing.\nDiscussion/literature review It is unclear how the different screen time behaviours, including multi-tasking, are associated with different measures of cognition, and what is the role of parents and educators in setting limits for each of these screen time behaviours. Do we need different limits for screen time duration and the type of media, with regard to on-line learning vs. “staring at screens”? What is the role of parents and educators here and do we set different rules? We would highly recommend to provide such a review.\nTable 2: More descriptive information on the sample of each article would be helpful (e.g. sample size, sex, country etc.). Also, other information on the study (e.g. type of control, setting, year of data collection, study design etc.). If longitudinal study, what is the cohort duration? Why were these studies included? More importantly, such a table for the role of parents and educators is needed as well.\nPage 4, 2nd paragraph: “The ‘right’ amount of screen time depended on the age and maturity of the child, the kind of content the child was consuming, their learning needs and family routine (Australian Government, Office of the eSafety Commissioner, 2021b, p.1)…”\nI think it is necessary to elaborate more on which type of content and learning needs the author is referring to.\nMinor comments:\nTitle: I would suggest to include the type of the review conducted in the title, to inform the reader early in the paper. Also, I suggest removing the age group from the title.\nIntroduction:\n\nFirst paragraph: Second sentence again implies that this article investigates the effects of screen time on child’s development. I suggest rephrasing to make clear that this paper is a review article. Moreover, first paragraph already presents the aim and motivation of the current paper without first explaining why screen time represents an important part of children’s daily activities and its potential role in their health outcomes. I suggest moving this paragraph later in the introduction, more precisely before the section on discussion/literature review.\nSecond paragraph: Please mention the type of articles/studies that are considered in this review.\nSecond sentence: “…longitudinal studies are included from studies of children who are both younger and older, that is, from before and after the primary (elementary) school years.”\nUnclear. Please rephrase. Did the author include only longitudinal studies for this review? From table 2, it does not seem to be the case. Moreover, this information should belong under the methods section and not in the introduction.\nFourth paragraph: Sentences are too long. Please consider rephrasing for clarity.\nSixth paragraph: Please clarify what are the Physical Synchronous, Physical Asynchronous, Cyber Synchronous and Cyber Asynchronous modalities. It can help the reader understand how ICT helps to optimize the students' learning processes.\nDiscussion/literature review\nFirst paragraph: “The literature is analysed from two perspectives. First, the current screen time recommendations for 6-to-12-year-old children are established.”\nI suggest rephrasing. The recommendations have been established by respective authorities or organisations. The author is discussing them in the current review. The review analysis strategy belongs to the methods section.\n“Second, to determine the effects of screen time on the brain development and cognition of young children, research findings from Neuroscience, Psychiatry, Psychology and Paediatrics are presented. Finally, a summary of this literature, based on a comparison of the two perspectives, is made to identify best practices. I now turn to these tasks.”\nPlease rephrase to make clear the current article is a review of the literature investigating the effects of screen time on the brain development of young children. Indicate what type of studies are considered for the review: Randomised controlled trials (RCT), observational studies (longitudinal, cross-sectional), case-control studies, systematic reviews, grey literature etc. Consider removing the sentence “I now turn to these tasks.”\nPage 3, 4th paragraph: “Such limits were intended to ‘reduce the risks of obesity, lost sleep, and impaired school performance’, while allowing children to ‘connect online with friends and family and learn about the broader world’. The goal was to keep children off their devices, that is ‘unplugged’, for at least 2 hours per day (Christakis, Medscape Medical News, 2016, p.1).”\nUnclear. Please rephrase to make clear that the recommendation was such that children should not spend more than 2 hours per day with screen devices. As it is written here, it implies the contrary.\nTable 1: I suggest also including the new recommendations from 2016, issued by AAP, which will help the reader to understand how the recommendations changed from 2013 to 2016.\nAgain, no difference between introduction, discussion and conclusion. Please streamline that.\n\nPage 4, 5th paragraph: “Correspondingly, ‘reductions in cortical thickness’, across prefrontal, parietal, and temporal regions of the brain that was attributed to ‘social deprivation in early life’, was associated with attention deficit hyperactivity disorder (ADHD) approximately four or five times more often than other children (McLaughlin et al., 2014, p.8).”\nUnclear. Please rephrase.\nPage 5, 5th paragraph: Please explain what measures of cognition were investigated in the respective studies. Also, which problem behaviours were the authors referring to?\nPage 5, 6th paragraph: \"The ‘digital distractions and supernormal capacities for cognitive offloading’ offered during screen time, created a ‘non-ideal environment’ for the ‘refinement of higher cognitive functions during critical periods of brain development’ in children and adolescents (Firth et al., 2019, pp.126-127).\"\nI suggest to elaborate further on the critical periods of brain development in children and adolescents. Which periods are considered critical and why? Where is the role of parents and educators in tackling the digital distractions?\nPage 6, 1st paragraph: “Extensive screen time and use of technology were correlated with ‘heightened attention-deficit symptoms’, ‘impaired emotional and social intelligence’, ‘technology addiction’, ‘social isolation’, ‘impaired brain development’, and ‘disrupted sleep’, while ‘background media’ had a negative impact on ‘cognitive load’ and ‘attentional capacity’ (Lissak, 2018, p.149-157)”\nPlease explain what “background media” refers to. Also, I suggest using the term “duration of screen time” instead of “length of screen time”.\nPage 8: “Finally, having established wide variance between the science on screen time and current practice, the question is how do we close the gap?”\nBased on the knowledge gained from this review, what are the author’s suggestions and recommendations to address this question?\n\nI suggest harmonising the use of terminology throughout the manuscript. The author uses “screen time”, “digital media use”, “use of technology” etc., all at the same time. I find the use of quotation marks excessive. Please consider removing where appropriate throughout 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? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "195897",
"date": "07 Sep 2023",
"name": "Jordy Kaufman",
"expertise": [
"Reviewer Expertise Child development",
"cognitive neuroscience",
"child-computer interaction"
],
"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 submitted manuscript aims to review the effects of screen time on the brain structure, cognitive abilities, and psychological well-being of children aged 6-12. This is a multifaceted and highly relevant topic, especially in the context of increasing screen exposure among children in the digital age. Despite its timely subject matter, the manuscript exhibits several shortcomings that impact its scholarly rigor and practical value.\n\nMy evaluation focuses on the clarity of the paper's objectives, the representation and selection of existing literature, as well as the accuracy and comprehensiveness of the arguments presented. While the majority of my critique centres on the manuscript's coverage of neurostructural and cognitive impacts, similar issues are present in the section on psychological effects.\nTo begin with, the paper's rationale and objectives are unclear. The title suggests a focus on the \"role of parents and educators,\" which the paper does not cover substantially. Likewise, the abstract sets an expectation that the paper will evaluate the extent to which current guidelines for child screen time are informed by research in multiple disciplines but does not fulfil this objective.\nHowever, my most critical concern is the manuscript's representation and selection of existing literature. The manuscript seems to selectively draw from studies without clearly outlining the criteria for inclusion or exclusion, which affects the comprehensiveness and balance of the review. Additionally, many of the cited studies are inaccurately represented. The manuscript also does not distinguish between the credibility of peer-reviewed articles and online news pieces, treating both with similar weight. Moreover, the reviewed research is discussed at a very superficial level. Indeed, the main criterion for inclusion in this review seems to be that the paper (or news article) includes at least one line of text that can be quoted to make a rhetorical case that screen usage is damaging to children.\n\nBelow I will detail examples of these issues in the sections that aim to review how screen usage affects brain structure and cognition.\nExample 1: \"Neuroimaging technologies, specifically 'Magnetic Resonance Imaging' (MRI) and 'functional MRI' (fMRI), have provided evidence that correlate screen time with 'structural changes' in the brains of children aged 0-18 years (Raschle et al., 2012, p.2).\"\nThe cited paper (Raschle et al., 2012) does not discuss screen time at all, making this an inaccurate representation of the source material.\n\nExample 2: : \"Lower microstructural integrity’ of brain white matter tracts were identified in children, aged 3-to-5 years, who used more than the screen time recommended by the AAP (2016b), that is, more than 1 hour per day without parental interaction (Hutton et al., 2019, p.8)\"\nThe manuscript selectively discusses findings from Hutton et al. (2019), focusing on the negative aspects of screen time while omitting the fact that Hutton found no significant effects of screen usage on cognition. Additionally,the manuscript fails to explain that because Hutton's study is correlational, conclusions regarding causality can not be drawn.\nThe manuscript also implies that children who deviate from AAP screen usage recommendations show different outcomes than those who adhere to them. However, Hutton’s study did not include any children who fully adhered to AAP guidelines. Also, the absence of reported effect sizes in Hutton's study makes it difficult to evaluate the practical significance of the findings. A more useful explanation of Hutton et al. would include report all relevant effects and null findings and highlight the limitations related to sample composition and the lack of effect size reporting. This would help readers understand the scope and limitations of these findings more clearly.\nExample 3: \"Average screen time for these children was slightly more than 2 hours per day but ranged from 1 hour to slightly more than 5 hours per day. Tracts that supported ‘language and emergent literacy skills, cognition, and executive functions’, were ‘more disorganized and underdeveloped\"\nThe manuscript uses the terms \"disorganized\" and \"underdeveloped\" in a way that makes it seem like they came from the Hutton et al. paper--which they did not. These terms are sourced from a CNN article summarizing Hutton's work rather than the study itself.\nAdditionally, the manuscript suggests that these outcomes are associated with exceeding the AAP's recommended amount of screen time, although Hutton’s study did not make a direct comparison between children who adhered to these guidelines and those who did not.\nTo maintain academic rigor, it's crucial to accurately represent the findings of the original studies. Using sensationalized or imprecise terms borrowed from news articles can mislead the reader. It would be beneficial to correct this and cite the original study's language and conclusions more faithfully.\nExample 4: \"Screen time, it was concluded, was 'too passive' for brain development, and 'displaced' other experiences that could have 'helped children reinforce brain networks more strongly' (Hutton, LaMotte, CNN News Health, 2019, p.1).\"\nThe manuscript inaccurately attributes conclusions to the peer-reviewed paper by Hutton that are not present in the original work. Instead, these statements are drawn from a CNN News Health article. Furthermore, even in that CNN piece, the language used is speculative, stating that screen time \"could be\" too passive rather than definitively concluding that it is.\nTo maintain the integrity and credibility of the manuscript, it is crucial to cite the original academic sources accurately and avoid drawing conclusions unsupported by those sources. The manuscript should either correct this misrepresentation or rely more closely on the language and findings of the original, peer-reviewed work.\nExample 5: \"Premature 'thinning' of the cerebral cortex, that is, cell loss or 'atrophy' in the outermost layer of the brain was identified through neuroimaging in children aged 9-to-10 years who used screen-based media for more than 7 hours per day (World Economic Forum, 2018, p.1).\nThe manuscript cites a web-based article press-release from the \"World Economic Forum\" to support this claim, which, in turn, is based on a CBS news segment that discusses preliminary findings from an NIH study. This chain of citations raises concerns about the verifiability of the information, especially as the manuscript does not provide a direct link to the NIH study itself.\nTo enhance the manuscript's credibility, it should directly cite peer-reviewed scientific studies whenever possible, especially for key claims. If the NIH study is published, a citation to the original research would substantiate this point more robustly.\nExample 6: \"Similarly, 'structural deficits' in the cortex, identified through neuroimaging, were attributed to excessive online gaming in Chinese adolescents and young adults. 'Decreased left orbitofrontal grey matter volume' was found after 6 weeks of daily online gaming in both 'excessive gamers' and 'gaming-naïve' subjects (Zhou et al., 2017, p.100-109;).\"\nGiven that the manuscript's title indicates a focus on children aged 6-12, the relevance of a study in which the average age of participants was 24 years is unclear. Additionally, while Zhou's study did show some grey matter changes after gaming exposure, this evidence emerged only in an exploratory analysis after the main analysis did not find a time-point by group interaction. This suggests that the evidence cited in the manuscript is quite weak and must be interpreted cautiously.\n\nExample 7: \"Correspondingly, ‘reductions in cortical thickness’, across prefrontal, parietal, and temporal regions of the brain that was attributed to ‘social deprivation in early life’, was associated with attention deficit hyperactivity disorder (ADHD) approximately four or five times more often than other children [...] it is not observed in otherwise healthy children.\"\nNone of the text above relates to screen usage despite it being in a section of the paper that is meant to describe what is known about screen usage effects.\n\nExample 8: \"Research from animal models (Waxmonsky, 2019, p.1) found frequent exposure to rapidly changing audio and visual bombardment, the hallmarks of many television shows and video games, had prevented brain nerve tracks from developing as intended. These findings, when extrapolated to brain development in children, pointed to ‘what children were not doing’, and ‘what was not happening in their brains’, because they were ‘staring at screens’. It was concluded that there was ‘nothing inherently beneficial about viewing screens’, rather, ‘a matter of how much risk’ screens posed (Waxmonsky, 2019, p.1-2).\"\nThe manuscript cites a news article by Waxmonsky (2019) as if it were a scientific study, which could mislead readers into thinking that the conclusions drawn are supported by peer-reviewed research. The news article itself does not present any original data or references and even acknowledges the need for further research. Citing such an article and representing it as describing research with firm conclusions undermines the manuscript's scientific integrity.\nExample 9: \"In Australian research, the synchronisation of social and emotional networks in the brain was correlated with active human engagement, known as ‘interpersonal neural synchronisation’ or neural coupling (Kerr, 2019, p.14). Physical face-to-face interactions ‘activate different parts of the brain’ that are not activated during virtual meetings (Hasson et al., 2012, pp.6-8).\"\nThis passage is problematic on multiple fronts. First, the passage does not address the manuscript's stated focus on the effects of screen time on children aged 6-12. Second, The Kerr (2019) reference provided leads to a dead link, making it impossible to evaluate the claim. Third, the manuscript misrepresents the Hasson et al. (2012) study, attributing statements to it that are not present. In fact, Hasson et al. provide evidence that contradicts the manuscript's claim—showing brain synchrony even when one person is listening to an audio recording of another, thus challenging the assertion that face-to-face interaction is uniquely activating.\nExample 10: \"Intensive physical face-to-face interactions, when used within the Auditory-Verbal Therapy (A-VT) approach to teach Australian children (0-18 years) with hearing loss to listen and speak, built and strengthened neural pathways in the auditory area of the brain, in areas where cognitive growth and language development is promoted (Dornan et al., 2011, 2010, 2009, 2009, 2008, 2007). Notably, changes in the anatomical and physiological development of the brain, particularly the connection between the prefrontal cortex and executive function, were aligned with Piagetian child development theory (Bolton & Hattie, 2017, p.22). It was concluded, therefore, that the first years of life needed to be focused on human interactions, specifically ‘healthy and stimulating experiences’, to ‘build brain architecture’ that can operate at its ‘full genetic potential’ (Harvard University, 2008, p.2).\"\nThe information presented in this section is largely irrelevant to the section's stated focus on the effects of screen time on the brain structure of children aged 6-12. It seems to imply that children who use screens don't receive adequate face-to-face interaction with others. But, the manuscript has presented no evidence to support this. If such evidence was included, then aspects of the above passage could be pertinent in a discussion section that broadly addresses developmental factors.\nExample 11: \"Higher daily screen time across all screen types was correlated with ‘lower cognition’ in children aged 9-to-10 years, with those in the ‘high’ (7.2 hours per day) and ‘middle’ (2.9 hours per day) screen time groups rated ‘lower in cognition’ when compared to children in the ‘low’ (1.2 hours per day) screen time group (Walsh et al., 2020, p.4). Early data from the NIH 2018 study indicated ‘lower scores in thinking and language tests’ for children whose screen time was ‘more than 2 hours per day’ (CBS News, 2018, p.1).\"\nWhile the manuscript cites an important study by Walsh et al., it fails to address the correlational nature of the data. Correlational studies do not establish causality, and the manuscript should clarify this limitation when discussing such studies. Including the CBS News article is superfluous as it contains no scientific information beyond the Walsh study.\n\nExample 12: \"‘Heavy television use’ by Australian children was predictive of a ‘loss of reading of four months relative to peers two years later’, while ‘heavy computer use’ predicted a similar loss in numeracy two years based on a comparison of academic results from NAPLAN, the National Assessment Program Literacy and Numeracy (Mundy et al., 2020, p.11).\"\nThe manuscript cites an important and rigorous study by Mundy et al. but falls short in discussing the study's nuanced findings. Notably, the study found negative academic outcomes associated with television and computer use but failed to reveal negative effects related to video gaming. This distinction could be critical for the manuscript's audience, who may be interested in the specific types of screen usage that are problematic. Additionally, it would be beneficial to distinguish between academic performance and cognitive abilities when discussing the implications of screen time. The Mundy study did not measure cognitive ability, and the current discussion assumes that academic performance is driven primarily by cognitive ability.\n\nExample 13: \"Conversely, ‘superior global cognition’ was identified in Canadian children aged 8-to-11 years who ‘adhered to recommendations of physical activity of 1 hour per day, recreational screen time of 2 hours or less per day, and sleep of 9-11 hours duration per night’, while the ‘limiting of recreational screen time’ and the ‘encouragement of healthy sleep’ was correlated with ‘improved cognition’ (Walsh et al., 2018, p.6; Rodriguez-Ayllon et al., 2020, p.5).\"\nThe manuscript notably omits crucial information from the Rodriguez-Ayllon et al. study, a robust investigation involving more than 2500 children, which found no relationship between screen usage and any structural MRI data. This is a significant omission, especially given that a key purpose of this manuscript is to review the impact of screen time on brain structure.\nAs mentioned above, the Walsh study is entirely correlational and relies on parental reports for both screen time and behavioral outcomes. The manuscript does not highlight these important limitations. While the Walsh study suggests that encouragement of healthy sleep could lead to better cognition, it does not actually examine the effects of such encouragement, let alone demonstrate that an intervention that involves such encouragement has any effect on children's cognition. Lastly, the section incorrectly attributes findings to Canadian children when neither of the cited studies used Canadian participants.\nExample 14: \"The ‘digital distractions and supernormal capacities for cognitive offloading’ offered during screen time, created a ‘non-ideal environment’ for the ‘refinement of higher cognitive functions during critical periods of brain development’ in children and adolescents (Firth et al., 2019, pp.126-127).\"\nThe manuscript appears to selectively quote from Firth et al. (2019) to support a preferred narrative. The actual sentence in the cited paper is: \"the Internet's digital distractions and supernormal capacities for cognitive offloading *seem* to create a non-ideal environment for the refinement of higher cognitive functions during critical periods of children and adolescents’ brain development.\"\nBy omitting the word \"seem,\" the manuscript transforms a cautious, speculative statement into a definitive claim, which is misleading and could have implications for how the research is interpreted by readers.\nExample 15: \"'Complex and multi-method based visual stimuli’ on screens was associated with ‘overload on working memory’, ‘divided attention’ and ‘impaired recall’. The combination of ‘audio-visual graphics, text, and animations’ impeded the ability to ‘register, process, and remember information with accuracy’. Consequently, cognitive overload impacted the ‘quality of comprehension, prioritization, and deep-level processing of incoming information’. Short-term memory, in turn, could not be consolidated into long-term memory, and resulted in ‘poor processing and understanding of what was taught or said’ (Jha & Arora, 2020, p.1). It was argued ‘the screen should be the tool, not the teacher’ (Roseberry Lytle, University of Washington, 2015, p.1).\"\nThe manuscript cites Jha & Arora (2020) to make a series of strong claims about the cognitive impact of screen time. However, Jha & Arora is a letter to the editor and does not provide original data or analysis to support these claims. The citation to Roseberry Lytle from the University of Washington leads to a dead link and is not included in the references section of the manuscript. This paragraph lacks credible, empirical support for its claims and should be removed from the manuscript. The inclusion of such unsupported statements undermines the scientific rigor of the manuscript.\nThe manuscript's section on physiological and psychological effects suffers from the same shortcomings detailed in previous sections. It appears that the manuscript prioritises quotable content from studies over a nuanced and rigorous analysis of the research methods, types of screen activities, and inherent limitations of the studies cited.\nConcluding comments:\nA well-executed narrative review should provide a clear, informative overview of the current state of knowledge on a particular topic, summarising existing studies while highlighting gaps, inconsistencies, and avenues for future research. By synthesising and interpreting existing data, a narrative review ideally offers new perspectives and insights that can guide future investigations and inform practitioners. Unfortunately, while this manuscript aims to tackle an important and timely issue, its surface-level and highly selective approach to the literature lacks the rigor, comprehensiveness, and balanced perspective that are critical for a narrative review to make a meaningful contribution to the field.\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?\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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-21
|
https://f1000research.com/articles/11-20/v1
|
10 Jan 22
|
{
"type": "Research Article",
"title": "Comparison of effects of medicinal cannabis or standard palliative care on quality of life of patients with cholangiocarcinoma in Northeast Thailand",
"authors": [
"Narisara Phansila",
"Chaiyasit Sittiwet",
"Ranee Wongkongdech",
"Narisara Phansila",
"Chaiyasit Sittiwet"
],
"abstract": "Background: Cholangiocarcinoma (CCA) has a poor prognosis and is a major cause of mortality and suffering in Thailand’s Northeastern (Isaan) Region.\n\nMethods: This prospective cohort study aimed to compare the health-related quality of life (HRQoL) among 72 newly diagnosed CCA patients; 42 patients who received cannabis treatment (CT) and 30 patients who received a standard palliative care treatment (ST). The study was carried out between 1st September 2019 to 31st October 2020. Data were collected from patients from oncology clinics of six hospitals in five provinces of northeast Thailand. The HRQoL was measured at baseline, and at 2 and 4 months after diagnosis by the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaires QLQ-C30, and QLQ-BIL21. The Mann-Whitney U-test was performed to compare quality of life scores between the two patient groups and Wilcoxon signed rank test was performed to compare within groups QoL scores at pre-treatment, and 2 and 4 month follow-ups. Results: Global health status and functional scales, for both groups were high at pre-treatment. At 2 and 4 month follow-up, CT group patients had consistent statistically significantly better Palliative Performance Scale (PPS), and QoL scores, and many symptom scores than the ST group.\n\nConclusions: Medicinal cannabis may increase QoL for advanced CCA patients. Our findings support the importance of early access to palliative cannabis care clinic before the terminal and acceleration phase close to death.",
"keywords": [
"Quality of life",
"Cholangiocarcinoma",
"medicinal cannabis",
"Northeastern Thailand"
],
"content": "Introduction\n\nCholangiocarcinoma (CCA) is a rare liver tumor worldwide (incidence <6 cases per 100,000), but, is highly prevalent in parts of Thailand.1 The Northeastern (Isaan) region of Thailand has > 85 cases per 100,000, especially in Khon Kaen Province with 118.5 cases per 100,000 populations. Which is 100 times higher than the global rate.2 Typically, CCAs are asymptomatic in the early stages, and are consequently not diagnosed until late stage when the cancer has already metastasized, severely limiting effective therapeutic options and becoming a major cause of mortality.3 The median post-surgery survival of CCA patients is about 4–5 months4; 5 and the 6-month survival is only 35%.5 The major surgical treatments are surgical resection and/or liver transplantation, whereas chemotherapies are virtually palliative given the typical late-stage diagnosis and marked chemo-resistance of this cancer.6\n\nQuality of life (QOL) is a broad multidimensional concept which includes subjective evaluations of both positive and negative aspects of life7 Health Related QOL (HRQoL) scales can be used as clinical assessments for new treatment efficacy or for well-being before and after an intervention, and have been used with hepatobiliary cancer.8\n\nMedical cannabis has been used in palliative care to alleviate pain, relieve nausea and stimulate appetite,9 and has been shown to attain good symptom control and reduce the number of palliative care drugs used.10 A recent oncology study on the short-term outcomes of medical cannabis showed significant improvement in multiple symptoms between baseline and one-month follow-up, including reductions in pain intensity, affective and sensory pain, improved sleep quality and duration and reduced cancer distress, and both physical and psychological symptom burden.11 However, no studies have yet compared the quality of life of patients with advanced CCA treated with, either, a standard palliative-care treatment protocol, or, with medical cannabis.\n\nThailand was the first country in Southeast Asia to approve cannabis for medical treatment.12 Currently, in Thailand, there are two palliative care treatment protocols allowed for cancer patients; standard treatment regime, and medical cannabis treatment. As there is no comparative Thai research yet on HRQoL from the perspective of patients, this study was designed to compare the perceived quality of life outcomes between the two treatment protocol options.\n\n\nMethods\n\nThis was a prospective cohort study using face-to-face interview questionnaire data from 72\n\nThe EORTC QLQ-C30 was used to assess patients with palliative cholangiocarcinoma. In the group with similar characteristics to the sample of both groups of 15 people each, the data were the mean and the variance, entering the aforementioned formula. by doing a pilot study\n\n∆ = different QOL both broup = 10.0\n\nα = α error = 0.05 (1.65)\n\nβ = β error = 0.2 (test power 0.80) (0.84)\n\nSamples were used in each study group of 30 people.\n\nWhen calculating the total sample size, which was the sample in the 4th month data collection, but because it was a forward study and the selection of target groups to participate in the study was Liver and bile duct cancer patients with a PPS score greater than or equal to 50 predictive of life expectancy greater than or equal to 60 days and from the literature review, it was found that The median survival for cholangiocarcinoma patients after palliative treatment was 4 months (95%CI = 3.6-4.6). Survival rates after palliative treatment were 3 and 6 months. equal to 59 percent (95%CI = 55.5-62.6), 39 (95%CI = 35.1-42.1) (Nat Thanyahan, 2013) The researchers estimated the likelihood of the target group dying while collecting data in the fourth month was 50%. Therefore, the study sample size was increased to 30 plus 15 per group equal to 45 people in the first sample data collection. that have completed until the end of the data collection and analysis of the study results must have a sample of more than or equal to 30 people (Figure 1).\n\nCCA = Cholangiocarcinoma; PPS = Palliative performance scale; ST = Standard treatment; CT= Cannabis treatment.\n\nCCA out-patients receiving either a standard palliative care treatment regimen, or medical cannabis treatment. Participants were recruited between September 2019 to 31st October 2020 from the four tertiary hospitals and two of the secondary hospitals serving five provinces of Northeast Thailand (Roi-Et Regional Hospital, Burirum Regional Hospital, Surin Provincial Hospital, Sawang Dandin Crown Prince Hospital, Panna Nikhom Hospital and Pana Hospital). They were recruited by clinicians upon late-stage CCA diagnosis, based on a diagnostic result from at least one of six procedures namely; ultrasonography (U/S), computerised tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangio -pancreatography (ERCP), and histology.13 and PPS score > 50. Patients had treatment plan options explained to them, such as chemotherapy, surgery, radiation therapy, morphine/other pain relief, or medical cannabis treatment and made their own selection. Depending on their choice, patients were then referred to either the hospital’s palliative care clinic or the medical cannabis clinic for treatment management. Medical cannabis clinic services are available in all hospitals affiliated with the Ministry of Public Health in Thailand. Doctors and patient care teams are trained and registered to prescribe using cannabis pre-assessment, treatment, and follow-up side effects and adverse reactions guidelines (http://www.lpnh.go.th/files/cmorph/SR.pdf). The medical cannabis treatment protocol has 3 regimens: 1) THC (1 ml = THC 12.5 mg), 2) THC: CBD 1:1 (1 ml = THC 27mg: CBD 25mg), 3) DTAM GANJA OIL (DEJA) (1 ml = THC 2 mg ± CBD 0.5 mg) (https://cannabis.fda.moph.go.th/) A doctor, or Thai traditional medicine practitioner is the one who prescribes treatment according to the guidelines.\n\nAns = Initiation of medical cannabis extracts in end-stage patients with various diseases who have never have been extracted from cannabis before (cannabinoids naive) is a small dose of medicinal cannabis extract to stimulate. The endocannabinoid system is based on three dosing principles (Reference: Cyr C, et al. Cannabis in palliative. care: current challenges and practical recommendations. Ann Pall Med 2018;7:463-77.)\n\n1. Start low: no exact starting dose. depending on the characteristics of each patient\n\nInitiate the smallest amount of medication that can be divided into individual products. The frequency or number of doses depends on how many hours can each medicinal cannabis extract be active in the body to manage pain, patients must be given medicinal cannabis extracts. to be effective continuously for 24 hours (around the clock)\n\n2. Go slow: adjusting the drug slowly until the appropriate dose is obtained. with symptom assessment designated as indications for individual use of medicinal cannabis extracts according to advance care plans If still does not improve, increase the dose gradually every 1-2 days (titration) until the effective treatment of the symptoms of interest. This should be adjusted. Medical cannabis extract dosage causing the patient to feel that they have a satisfactory quality of life within the period about 2 weeks If the patient has symptoms of dizziness, loss of coordination, slow heartbeat, abnormal blood pressure, disorientation, agitation, hallucinations from medical cannabis extracts stop increasing the cannabis extract dosage and reverse the dose. Go down one step and assess the symptoms that are indicated as indications. Case of cannabis extract used causing side effects ineffective in treating the symptoms according to the indications prescribed or not likely to improve at all within a period of time of the 2-week dosage adjustment. The use of medicinal cannabis extracts in patients should be discontinued by a slow reduction in dosage every 1 to 2 days (tape off)\n\n3. Stay low: maintain dosage and dosage of medicinal cannabis extract at patient levels. Feeling that the symptoms that are specific to the individual indication have decreased The patient had a satisfactory quality of life. If the symptoms are indicative. If recurring, consider taking a 48-hour break from medicinal cannabis extracts, known as drug holidays. By reducing the dose slowly over about 1 week to prevent the side effects of stopping the cannabis extract. Sudden medical After stopping the drug for approximately 48 hours, resume using the medical cannabis extract. Again in small quantities and gradually increase the drug with the same method\n\nProcedure for prescribing cannabis extract in end stage palliative patients\n\n1. Patients with terminal diseases who are likely to benefit from the use of cannabis extracts When there is no prohibition to use is metastatic or recurrent cancer, code C00-C96, emphysema (COPD), ICD-10, code J44.and full AIDS patients, code B22-B24, undergo a drug risk assessment screening at a cannabis clinic. no risk found\n\n2. Consulting the palliative care team\n\n3. Palliative care team make family meeting and advance care plan. Evaluate 11 Edmonton Symptom Assessment System (ESAS) symptoms and side effects.from cannabis extract Scored according to the patient's feelings at the time of assessment, from 0-10, the system must force the assessment. Every symptom, every time, the system collects data for each symptom in numerical base. and displayed in colors or symbols for convenience to adjust medication\n\n\n\n1. There is no exact starting dose for each cannabis product. The appropriate dosage depends on characteristics of each patient and adjusted for each product. Start with a low dose and increase the dose slowly until the dose is reached. suitable for the highest therapeutic effect and the lowest side effects Low doses are less likely to cause side effects (http://www.mhso.dmh.go.th/fileupload/20210129308824218.pdf)\n\nWe assessed quality of life with the EORTC QLQ-C30, QLQ-BIL-21 before treatment commenced and re-evaluated at the end of the 2nd and 4th month of treatment. We excluded patients when Palliative Performance Scale (PPS) scores were less than 30 (PPS<30 median survival time of 13 day)14 at the 2nd and 4th month, or, when patients were admitted to hospital, patients died, refused to continue, or, were lost to follow-up for unknown reasons.\n\nThe QOL data was collected using the EORTC QLQ-C30 (version 3.0), and the QLQ-BIL21. The EORTC QLQ-C30 (v 3.0) is one of the most widely used patient self-report quality of life outcome scales. The EORTC QLQ-C30 assesses five functional domains: ambulation ability level, extent of disease, self-care, food and fluid intake, and level of consciousness. PPS is measured in 10% decrements from 100% (fully ambulatory and healthy) to 0% (death). It is simple and practical for palliative care patients15 and one of the most studied prognostic tools in palliative care, and is in common use in Thailand.16 The QLQ-BIL21 contains: 3 single item assessments relating to treatment side effects, difficulties with drainage bags/tubes and concerns regarding weight loss, in addition to 5 proposed scales: eating symptoms (4 items), jaundice symptoms (3 items), tiredness (3 items), pain symptoms (4 items) and anxiety symptoms (4 items).17 The scores were linearly transformed to a score between 0 and 100. For the functional and global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden.18\n\nPatients were divided into two groups according to their scores; those who scored < 33 on the functional scales and on the global QoL were considered to have low QoL, while patients who scored > 66 were considered to have higher QoL. For symptom scales, the scoring was reversed, i.e., those who scored < 33 were considered in better health and the patients who scored >66 had high symptom burden.19\n\nThe QOL data was collected by specially trained research assistants in each hospital at the time of enrollment into the study, and by the researcher in hospital, or, in the community among survivors at 2 and 4 months’ post-treatment. Research monitoring and quality control procedures included the researcher observing research assistants’ first interview before treatment and researcher carrying out follow-up interviews at 2 and 4 months post-treatment commencement.\n\nDescriptive statistics was used to present patients’ demographic characteristics. Percentages were used to describe categorical data and means with standard deviations or medians with ranges were used to describe continuous data. The Mann-Whitney U-test was used to compare quality of life scores between the two patient groups and Wilcoxon signed rank test performed to compared QoL score within groups at pre-treatment, 2, and 4 months. All calculations were carried out using SPSS (v.24).\n\nThis research was approved by the Maha-Sarakham University Human Research Ethics Committee (Reference NO.204/2563) and Roi-Et Regional Hospital, and Burirum Regional Hospital (Reference RE064/2563) Ethics Committees for Human Research, based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines Written informed consent was obtained from all patients.\n\n\nResults\n\nInitially, 52 patients chose a standard treatment (ST), and 63 patients chose medical cannabis treatment (CT), all with Palliative Performance Scores (PPS) > 50. However, by the four-month follow-up point, there were only 72 patients remaining (21 dropped out at the 2nd month, and a further 12 at 4 months), leaving 30 patients in the ST group and 42 in the CT group, respectively. In total, 30 patients were in the ST group (15 males and 15 females) and 42 patients in the CT group (27 males and 15 females). Their mean ages were 66.03 (S.D. = 11.46) and 65.80 years (S. D. = 10.55), respectively. Most patients were single/widowed (66.64%/59.52%) and worked in agriculture (50.0%/52.38%). Mean PPS scores were 79.33 (S.D. = 5.83) and 80.23 (S.D. = 12.78), respectively. Table 1 displays fuller demographic characteristics of the 72 CCA patients.\n\nComparison of variables in EORTC QLQ-C30, QLQ-QLQ-BIL21 at the pre-treatment, 2nd and 4th month treatment (Table 2).\n\n* P value <0.05 were statistically significant.\n\nAt baseline, there were no statistically significant PPS, QoL, or symptom differences between the two groups on QLQ-C30, and QLQ-BIL21 except for higher cognitive functioning in the ST group over the CT group (p = 0.046).\n\nAll global health status and functional scores were >66, indicating higher QoL, while all symptom scores were moderate to low. Higher symptom scale scores indicate lower QoL.\n\nThe CT group had statistically higher scores for both PPS and QoL than the ST group after 2 months (80.24 ± 12.97; 59.00 ± 9.59, p = 0.010).\n\nIn the functional domain, emotional and social function scores were also statistically significantly higher than for the CT group over the ST patients. The CT group now also had statistically significantly lower scores (better QoL) on 7 symptom scales: fatigue, insomnia, appetite loss, constipation, eating, tiredness and weight loss.\n\nFour months after treatment commenced the CT group again had statistically significantly higher PPS and QoL scores than the CT group (68.09 ± 26.79; 41.66 ± 18) (p < 0.010). Most notably, the CT group now also had significantly higher scores on all five Global Health Status QoL function scales: physical, role, emotional, cognitive and social functioning. The CT group also had statistically significantly lower scores (better QoL) on 8 symptom scales: fatigue, dyspnea, insomnia, appetite loss, constipation, eating, tiredness and weight loss.\n\n\nDiscussion\n\nTo our knowledge, this is the first multi-center study comparing the effects of standard palliative care versus medicinal cannabis treatment on QoL on patients with advanced CCA. The two groups had little difference at baseline but at 2- and 4-month follow-ups the CT group consistently self-reported higher global health status and functional behaviors, and lower illness/symptom-related scores than the standard palliative-care group.\n\nThe CT regimen for our CCA patients was associated with meaningful improvements in health-related QoL consistent with previous improvements seen in pain reduction, quality of life, social life, and activity levels with other chronic pain patients.20 From the second month of treatment our CT patients rated improvements in fatigue levels, insomnia, appetite loss, constipation, eating tiredness and weight loss. There was also a significant improvement in dyspnea at the fourth month, maybe due to cannabis’ beneficial effect on appetite, sleep and rest.21 Other cannabis studies have shown more than 10% weight gain,22 and cancer patients feeling refreshed, less fatigued and having reduced side-effects such as nausea, vomiting, and loss of appetite from treatment.23 Cannabinoids can also stimulate a therapeutic response via immune response enhancement.24 This is relevant due to current standard chemotherapy treatments which increase inflammation in all body systems with consequent intellectual impairments including attention, memory, decision making, risk management, fatigue, lack of motivation and peripheral nerve inflammation.25 Cannabis or its derivatives have been widely used by patients with advanced cancer to help with cancer symptoms and treat side effects24 and patients affirm its use for pain, anxiety, depression, and significantly prefer it over antianxiety medications.26 It is also reported as useful for nausea, sleep, appetite stimulation,26 and even at one-month follow-up, most parameters have been shown to improve significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden.11\n\nWe found no inter-group differences in pain ratings between the second- and fourth-month follow-ups. Pain is one of most common symptoms associated with cancer27 and is one of the symptoms patients fear most.28 Unrelieved pain denies patients comfort and greatly affects their activities, motivation, social interactions, and overall quality of life.28 Pain management goals are, therefore, is to reduce pain to a level that allows for an acceptable quality of life, and both CT and ST treatments appeared to do this satisfactorily. The benefit of pain relief must be balanced against the risk of adverse side-effects and overdose. Opioid analgesics are essential for the adequate treatment of moderate and severe cancer pain, however, despite good opioid control of baseline pain, some patients do have short-term, short-lived, intense pain episodes. A recent study on cannabis palliative care in oncology patients, had similar findings, suggesting that medical cannabis reduced chronic or neuropathic pain in advanced cancer patients29 with significant improvements in other assessed parameters, including reduced pain intensity, improved sleep, and a decrease in pharmaceutical analgesics consumption.11\n\nThere was no inter-group difference in anxiety ratings between the second- and fourth- month follow-ups for our patient groups. Anxiety is common in cancer patients and greatly influences survival rate, adherence to treatment, and quality of life. Advanced stage cancer patients, and those with metastasis, are more likely to have higher levels of anxiety than those with no sign of metastasis.30 Some research on cannabis use in surviving cancer patients has found it alleviated 41.6% of anxiety symptoms,44 however, research on cannabis use for anxiety and depression is currently limited, and there are many confounding factors. In addition, depression and anxiety are both normal and common responses to a cancer diagnosis, and therefore diagnosing clinical levels of anxiety and studying treatments to address these levels in the context of cancer is difficult.31\n\nIn addition to quality of life outcome differences between ST and CT, research also shows a range of potential patient CT palliative-care access issues. Most patients need oncologist or primary care physician consultations. Thus, the primary care physician needs to be qualified and have good knowledge and a positive attitude towards the use of cannabis treatment among these patients. In an Australian study, most doctors felt their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. GPs generally rated their medical cannabis knowledge as poor and shared care arrangements with a specialist, though supported medical cannabis use in chronic cancer pain and palliative care.32 Four themes were found to underpin reluctance to authorize medical cannabis in Canada; presumed lack of evidence, indications for therapeutic use, discomfort with therapeutic use and practitioner’s openness to emerging evidence.33 Importantly, patients deciding to use cannabis to alleviate cancer symptoms, desired the approval from their medical team. While some patients found their physicians were willing to prescribe cannabis, or, refer them to a medical cannabis expert, some found their physicians were unwilling to discuss a cannabis option for managing their cancer symptoms34 and, were not ready, or, did not want to answer patients’ questions about medical cannabis.35 Some clinicians feel hampered by a lack of clinically relevant information about cannabis use, efficacy, side-effects and have difficulty discussing the medicinal benefits of cannabis in a clinical settings.36 Another study found only 30% of oncologists felt sufficiently informed to make recommendations regarding medical cannabis treatment.21\n\nMost patients with advanced cancer experience symptoms throughout the disease trajectory, often with greater intensity as death approaches. If poorly managed, such symptoms can have a considerable impact on patients’ ability to function, their quality of life and ability to comply with anticancer treatments and use of health care resources.37 Medical cannabis is another option to relieve symptoms caused by the cancer itself, direct or indirect consequences of the cancer, early or late adverse effects of treatment, and/or comorbid conditions cancer treatment, especially late stage cancer. Medical cannabis has been shown to relieve symptoms caused by cancer, to reduce chronic or neuropathic pain in advanced cancer patients38 and to improve patients’ quality of life outcomes. Past medical cannabis treatment research evidence has been inconsistent and generally limited by poor quality, with large variations in cannabis-based products limiting the ability to make direct comparisons,39 as well as studies lacking statistical power and with small subject sizes, and recommendations against the use of medical cannabis as a first or second line option for palliative cancer pain or when other treatments have failed.40 Our study, found beneficial outcomes in a range of quality of life and symptom measures for cannabis treatment over standard palliative care protocols, using standardized medical cannabis products and treatment protocols.\n\nThis study has several limitations. One is the number of patients who dropped out before study completion likely due to rapid disease progression. Most patients were elderly and suffered from advanced CCA. Newly diagnosed CCA patients typically have a poor prognosis and short-term survival due to late-stage diagnosis. Registration for the standard palliative care clinic and/or cannabis clinic in each hospital also differs across physicians. Decision-making across patients, families, at different stages of disease, organ metastasis, and for methods of treatment also varies.\n\nTo the best of our knowledge, this is the first study to compare quality of life of CCA patients who received ST or CT and were monitored before treatment commencement and at 2nd and 4th month follow-ups and, across 8 hospitals, and 5 provinces. Medical cannabis products and usage was standardized under the Thai Food and Drug Administration regulations. The side effects, safety, benefits and harms of this cannabis have been reviewed and certified for patient treatment, by trained and Thai registered prescribers of medical cannabis.\n\n\nData availability\n\nFigshare: QOL of patients with cholangiocarcinoma _ DATA, https://doi.org/10.6084/m9.figshare.17162621.v1.41\n\nFigshare: QOL_document information, https://doi.org/10.6084/m9.figshare.17203922.v1.42\n\nThis project contains the research information sheet.\n\nFigshare: QOL_Inform consent, https://doi.org/10.6084/m9.figshare.17203931.v1.43\n\nThis project contains the consent form.\n\nFigshare: QOL_questionnaire, https://doi.org/10.6084/m9.figshare.17203934.v1.44\n\nThis project contains the questionnaire.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors would like to thank all patients and family colleagues in the Faculty of Medicine, Mahasarakham University especially the University Hospital Center of Excellence Team palliative clinic and cannabis clinic) for their invaluable help and encouragement throughout the course of this research. Finally, the authors express their appreciation for the participation of all patients in this research.\n\n\nReferences\n\nSripa B, Pairojkul C: Cholangiocarcinoma: Lessons from Thailand. Curr. Opin. Gastroenterol. 2008 May; 24(3): 349–356. PubMed Abstract | Publisher Full Text\n\nAlsaleh M, Leftley Z, Barbera TA, et al.: Cholangiocarcinoma: a guide for the nonspecialist. Int. J. Gen. Med. 2018 Dec; Volume 12: 13–23. PubMed Abstract | Publisher Full Text\n\nJansen H, Pape U-F, Utku N: A review of systemic therapy in biliary tract carcinoma. J. Gastrointest. Oncol. 2020 Aug [cited 2021 Nov 28]; 11(4): 770–789. PubMed Abstract | Publisher Full Text Reference Source\n\nMihalache F, Tantau M, Diaconu B, et al.: Survival and quality of life of cholangiocarcinoma patients: a prospective study over a 4 year period. J. Gastrointest. Liver Dis. JGLD. 2010 Sep; 19(3): 285–290.\n\nWoradet S, Songserm N, Promthet S, et al.: Health-Related Quality of Life and Survival of Cholangiocarcinoma Patients in Northeastern Region of Thailand. PLoS One. 2016; 11(9): e0163448. PubMed Abstract | Publisher Full Text\n\nCai Y, Cheng N, Ye H, et al.: The current management of cholangiocarcinoma: A comparison of current guidelines. Biosci. Trends. 2016; 10(2): 92–102. PubMed Abstract | Publisher Full Text\n\nwho_qol_user_manual_98.pdf: cited 2021 Oct 22. Reference Source\n\nChiu C-C, Lee K-T, Wang J-J, et al.: Preoperative Health-Related Quality of Life Predicts Minimal Clinically Important Difference and Survival after Surgical Resection of Hepatocellular Carcinoma. J. Clin. Med. 2019 Apr 27; 8(5): 576. PubMed Abstract | Publisher Full Text\n\nDariš B, Verboten MT, Knez Ž, et al.: Cannabinoids in cancer treatment: Therapeutic potential and legislation. Bosn. J. Basic Med. Sci. 2019 Feb; 19(1): 14–23. PubMed Abstract | Publisher Full Text\n\nDzierżanowski T: Prospects for the Use of Cannabinoids in Oncology and Palliative Care Practice: A Review of the Evidence. Cancer. 2019 Jan 22 [cited 2021 May 10]; 11(2). Publisher Full Text Reference Source\n\nAviram J, Lewitus GM, Vysotski Y, et al.: Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients. Pharmaceuticals. 2020 Nov 30 [cited 2021 May 15]; 13(12). PubMed Abstract | Publisher Full Text Reference Source\n\n2020 Global Cannabis Guide - Thailand|World Law Group: [cited 2021 May 17]. Reference Source\n\nBuettner S, van Vugt JLA , Ijzermans J, et al.: Intrahepatic cholangiocarcinoma: current perspectives. Onco. Targets Ther. 2017 Feb; 10: 1131–1142. PubMed Abstract | Publisher Full Text\n\nPrompantakorn P, Angkurawaranon C, Pinyopornpanish K, et al.: Palliative Performance Scale and survival in patients with cancer and non-cancer diagnoses needing a palliative care consultation: a retrospective cohort study. BMC Palliat. Care. 2021 Dec; 20(1): 74. PubMed Abstract | Publisher Full Text\n\nChan E-Y, Wu H-Y, Chan Y-H: Revisiting the Palliative Performance Scale: change in scores during disease trajectory predicts survival. Palliat. Med. 2013 Apr 1; 27(4): 367–374. PubMed Abstract | Publisher Full Text\n\nChewaskulyong B, Sapinun L, Downing GM, et al.: Reliability and validity of the Thai translation (Thai PPS Adult Suandok) of the Palliative Performance Scale (PPSv2). Palliat. Med. 2012 Dec 1; 26(8): 1034–1041. PubMed Abstract | Publisher Full Text\n\nKaupp-Roberts SD, Yadegarfar G, Friend E, et al.: Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder. Br. J. Cancer. 2016 Oct 25; 115(9): 1032–1038. PubMed Abstract | Publisher Full Text\n\nFayers PM: European Organization for Research on Treatment of Cancer SG on Q of L. EORTC QLQ-C30 scoring manual. Brussels.2001.\n\nFayers PM, Aaronson N, Bjordal K, et al.: EORTC QLQ-C30 scoring manual: this manual is intended to assist users with scoring procedures for the QLQ-C30 version 3 and earlier, and the QLQ supplementary modules. Brussels: EORTC; 2001.\n\nVigil JM, Stith SS, Adams IM, et al.: Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study. PLoS One. 2017; 12(11): e0187795. PubMed Abstract | Publisher Full Text\n\nBraun IM, Wright A, Peteet J, et al.: Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018 Jul 1; 36(19): 1957–1962. PubMed Abstract | Publisher Full Text\n\nBar-Sela G, Zalman D, Semenysty V, et al.: The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study. Integr. Cancer Ther. 2019 Oct 9 [cited 2021 May 10]; 18: 153473541988149. Publisher Full Text Reference Source\n\nAbrams DI, Guzman M: Cannabis in cancer care. Clin. Pharmacol. Ther. 2015 Jun; 97(6): 575–586. Publisher Full Text\n\nBar-Sela G, Cohen I, Campisi-Pinto S, et al.: Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancer. 2020 Aug 28 [cited 2021 May 15]; 12(9). Publisher Full Text Reference Source\n\nWilliams AM, Shah R, Shayne M, et al.: Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy. J. Neuroimmunol. 2018 Jan 314; 314: 17–23. PubMed Abstract | Publisher Full Text\n\nTanco K, Dumlao D, Kreis R, et al.: Attitudes and Beliefs About Medical Usefulness and Legalization of Marijuana among Cancer Patients in a Legalized and a Nonlegalized State. J. Palliat. Med. 2019 Oct 1; 22(10): 1213–1220. PubMed Abstract | Publisher Full Text\n\nSwarm RA, Paice JA, Anghelescu DL, et al.: Adult Cancer Pain, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2019 Aug 1; 17(8): 977–1007. PubMed Abstract | Publisher Full Text\n\nte Boveldt N : Pain and Its Interference with Daily Activitiesin Medical Oncology Outpatients. Pain Physician. 2013 Jul 14; 4;16(4;7): 379–389. Publisher Full Text\n\nBlake A, Wan BA, Malek L, et al.: A selective review of medical cannabis in cancer pain management. Ann. Palliat. Med. 2018 Jan; 6(2): S215–S222. PubMed Abstract | Publisher Full Text\n\nTruong DV, Bui QTT, Nguyen DT, et al.: Anxiety Among Inpatients With Cancer: Findings From a Hospital-Based Cross-Sectional Study in Vietnam. Cancer Control J Moffitt Cancer Cent. 2019 Jul 22; 26(1): 107327481986464. Publisher Full Text\n\nYoung K, Singh G: Biological Mechanisms of Cancer-Induced Depression. Front. Psych. 2018; 9: 299. PubMed Abstract | Publisher Full Text\n\nKaranges EA, Suraev A, Elias N, et al.: Knowledge and attitudes of Australian general practitioners towards medicinal cannabis: a cross-sectional survey. BMJ Open. 2018 Jul 3; 8(7): e022101. PubMed Abstract | Publisher Full Text\n\nNg JY, Gilotra K, Usman S, et al.: Attitudes toward medical cannabis among family physicians practising in Ontario, Canada: a qualitative research study. CMAJ Open. 2021 Jun; 9(2): E342–E348. PubMed Abstract | Publisher Full Text\n\nMcTaggart-Cowan H, Bentley C, Raymakers A, et al.: Understanding cancer survivors’ reasons to medicate with cannabis: A qualitative study based on the theory of planned behavior. Cancer Med. 2021; 10(1): 396–404. PubMed Abstract | Publisher Full Text\n\nPhilpot LM, Ebbert JO, Hurt RT: A survey of the attitudes, beliefs and knowledge about medical cannabis among primary care providers. BMC Fam. Pract. 2019 Jan 22; 20: 17. PubMed Abstract | Publisher Full Text\n\nCooke A, Knight K, Miaskowski C: Patients’ and clinicians’ perspectives of co-use of cannabis and opioids for chronic non-cancer pain management in primary care. Int. J. Drug Policy. 2019 Jan; 63: 23–28. PubMed Abstract | Publisher Full Text\n\nHenson LA, Maddocks M, Evans C, et al.: Palliative Care and the Management of Common Distressing Symptoms in Advanced Cancer: Pain, Breathlessness, Nausea and Vomiting, and Fatigue. J. Clin. Oncol. 2020 Feb 5 [cited 2021 Dec 4]; 38: 905–914. PubMed Abstract | Publisher Full Text\n\nBlake A, Wan BA, Malek L, et al.: A selective review of medical cannabis in cancer pain management. Ann. Palliat Med. 2017 Dec; 6(Suppl 2): S215–S222. PubMed Abstract | Publisher Full Text\n\nInglet S, Winter B, Yost S, et al.: Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature. Ann. Pharmacother. 2020 Jun 2; 54: 1109–1143. Publisher Full Text\n\nMacDonald E: Medical Cannabis Use in Palliative Care: Review of Clinical Effectiveness and Guidelines – An Update.2019 Oct 29 [cited 2021 Dec 4]. https://pubmed.ncbi.nlm.nih.gov/31873991/\n\nPhansila N, Wongkongdech R, Sittiwet C: QOL of patients with cholangiocarcinoma _ DATA. figshare. Dataset. 2021. Publisher Full Text\n\nPhansila N, Wongkongdech R, Sittiwet C: QOL_document information. figshare. Dataset. 2021. Publisher Full Text\n\nPhansila N, Wongkongdech R, Sittiwet C: QOL_Inform consent. figshare. Dataset. 2021. Publisher Full Text\n\nPhansila N, Wongkongdech R, Sittiwet C: QOL_questionnaire. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "223474",
"date": "30 Jan 2024",
"name": "Ueamporn Summart",
"expertise": [
"Reviewer Expertise Nursing and 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\nIntroduction: 1) What type of operation have you mentioned in this study? Please specify the survival rate of CCA patients (palliative or curative treatments) because the survival rate of curative resection is more than 1 year. 2) Paragraph 3: Please describe the association between pain, sleep, and HRQOL. Methods : 1) For sample size calculation, what is the primary outcome of your study? Why you use the sample size for Bonferini's test? 2) Please describe more details about the standard treatment that the participants in both groups received. 3) Please identify some details about how the participants enrolled in both groups (including inclusion and exclusion criteria). 4) For the tool that is used to measure QOL, why does the author consider this tool? (as the specific QOL tool for CCA patients is FACT-HEP.) 4) Statistical analysis: 4.1) Please review the statistical analysis that you used to compare the primary outcome (HRQOL). Why does the author use non-parametric, given the low power of the test, instead of parametric? (following the results of assumption test ?) 4.2) For repeated measures more than twice, please avoid\n\nstatistical testing more than once. I suggest that you can use the GEE ( the effect of dependency among observations that may cause ineffective and ineffective estimation of the parameter) and overestimate of the standard error (SE) for time-dependent covariates. Results 1) Table 1 : Due to the imbalanced baseline characteristics of the participants ( such as gender), how can we solve this problem? 2) Table 2 : Show the mean scores between 2 groups that seem comparable. Why does the author use non-parametric instead of parametric so that you can show the magnitude of the effect (such as the mean difference)? Discussion Please review this part: I think the main objective of this study was to compare the mean scores of HRQOL between two groups\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": []
}
] | 1
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https://f1000research.com/articles/11-20
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https://f1000research.com/articles/10-1102/v1
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01 Nov 21
|
{
"type": "Research Article",
"title": "Crystal structure of Pseudomonas aeruginosa FabB C161A, a template for structure-based design for new antibiotics",
"authors": [
"Vladyslav Yadrykhins'ky",
"Charis Georgiou",
"Ruth Brenk",
"Vladyslav Yadrykhins'ky"
],
"abstract": "Background: FabB (3-oxoacyl-[acyl-carrier-protein] synthase 1) is part of the fatty acid synthesis II pathway found in bacteria and a potential target for antibiotics. The enzyme catalyses the Claisen condensation of malonyl-ACP (acyl carrier protein) with acyl-ACP via an acyl intermediate. Here, we report the crystal structure of the intermediate-mimicking Pseudomonas aeruginosa FabB (PaFabB) C161A variant. Methods: His-tagged PaFabB C161A was expressed in E.coli Rosetta DE3 pLysS cells, cleaved by TEV protease and purified using affinity and size exclusion chromatography. Commercial screens were used to identify suitable crystallization conditions which were subsequently improved to obtain well diffracting crystals. Results: We developed a robust and efficient system for recombinant expression of PaFabB C161A. Conditions to obtain well diffracting crystals were established. The crystal structure of PaFabB C161A was solved by molecular replacement at 1.3 Å resolution. Conclusions: The PaFabB C161A crystal structure can be used as a template to facilitate the design of FabB inhibitors.",
"keywords": [
"crystal structure",
"3-oxoacyl-[acyl-carrier-protein] synthase 1",
"FabB",
"antibiotics"
],
"content": "Introduction\n\nNew antibiotics are urgently needed to maintain the high standard of living that we have got accustomed to as the antibiotics of today are losing effectiveness faster than they are being replaced by new treatment options.1 If no action is taken, by 2050 drug-resistant infections will kill 10 million people a year worldwide, more than currently die from cancer.2 A possible source for new targets for antibiotics is the fatty acid synthesis (FAS II) pathway (Figure 1A).3 In this pathway, fatty acid synthesis is carried out by a series of monofunctional enzymes which are highly conserved among microbial pathogens. Genes coding for enzymes in the FAS II pathway have been found to be essential for P. aeruginosa in several genetic screens, including the gene for FabB (3-oxoacyl-[acyl-carrier-protein] synthase 1).4–8\n\nA) Schematic overview of the elongation part of the FAS II pathway. B) Condensation reaction catalysed by FabF/B. (ACP: acyl carrier protein). C) Platensimycin and platencin have been reported as dual FabF/B inhibitors.\n\nBoth, FabB and FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2) catalyse the Claisen condensation of malonyl-ACP (acyl carrier protein) with acyl-ACP (Figure 1B), but differ in substrate specificity for the fatty acid chain.3 Platensimycin and platencin (Figure 1C) have been reported to be FabF and FabB inhibitors.9,10 However, it has been shown that these compounds do not bind potently to the w. t. enzyme, but only to the lauroyl-FabF intermediate (Figure 1B) and to intermediate-mimicking FabF variants in which the active site Cys has been changed to either Gln or Ala.9,11 It has been assumed that the same is the case for FabB.\n\nTo facilitate structure-based design of FAS II inhibitors, knowledge of the structures in this pathway is essential. Recently, we have reported the crystal structure of PaFabF and the reaction intermediate-mimicking variant PaFabF C164Q.12 Here, we report the crystal structure of PaFabB C161A at 1.3 Å resolution.\n\n\nResults\n\nThe gene coding for P. aeruginosa PA14 FabB C161A was synthesised and cloned in a bacterial plasmid pET-28a(+)-TEV vector after a DNA sequence coding for a 6-His-tag followed by a TEV cleavage site. To find good expression conditions, seven widely used E. coli strains were transformed with the plasmid (BL21 (DE3), BL21 (DE3) pLysS, C41 (DE3), C41 (DE3) pLysS, C43 (DE3), C43 (DE3) pLysS and Rosetta (DE3) pLysS) and screened for protein expression. The best results were obtained with Rosetta (DE3) pLysS cells (data not shown). Therefore, this cell line was used for all subsequent protein expression experiments.21\n\nHis-tagged PaFabB C161A was purified using affinity chromatography with a Ni column followed by size exclusion chromatography (SEC). To obtain FabB with a cleaved His-tag, the protein obtained after affinity chromatography was cleaved with TEV protease. The cleaved protein was separated from the protease and the tag by inverse affinity chromatography followed by SEC. In both cases, pure protein was obtained as judged by SDS-PAGE gel electrophoresis (Figure 2). Typical yields for His-tagged PaFabB C161A were 26 mg/L and for cleaved PaFabB C161A 7 mg/L.\n\nLane 1: PaFabB C164A (without His-tag) after inverse affinity chromatography, lane 2: 6-His-tagged PaFabB C164A after SEC purification, lane 3: PaFabB C164A (without His-tag) after SEC purification, lane 4: protein ladder.\n\nCrystallization trials of His-tagged PaFabB C161A and cleaved PaFabB C164A were attempted using the JCSG+, PACT premier, HELIX (only His-tagged PaFabB C161A) and LFS screens. No promising crystallization conditions for His-tagged PaFabB C161A were found using these screens. In contrast, 11 different conditions resulted in crystals of His-tag cleaved PaFabB C164A (Table 1, Figure 2). All of these conditions contained PEG 3350 between 20 and 25% and a number of conditions contained ethylene glycol. Further, the majority of the conditions contained 0.1 M Bis-Tris propane, and 0.2 M sodium iodide. Therefore, these components were kept for further optimization trials. The pH of the initial conditions varied from 5.5 to 8.5. As crystals grown in a buffer of pH 7.5 were visually judged to be more regular (e. g. the crystal shown in Figure 3B), this pH was fixed during optimization. These considerations resulted in an optimization matrix where the concentration of PEG 3350 was varied between 5 and 30% and the protein concentration between 9 and 23 mg/mL. Ethylene glycol was added to all conditions at either 10 or 20% while 0.2 M sodium iodide and 0.1 M Bis-Tris propane were fixed (Figure 4). Under 32 conditions, crystals were obtained. These were mounted and used for diffraction experiments.\n\n(PEG-polyethylene glycol; EG-ethylene glycol.)\n\nA) condition F3 from LFS, B) G3 from LFS, C) F3 from PACT premier, D) G3 from PACT premier (for composition of crystallization buffer see Table 1).\n\nThe numbers in the cells indicate the ratio between protein solution and crystallization buffer in the drops (drop 1-1:1 ratio, drop 2-1:2 ratio, drop 3-2:1 ratio). Coloured cells indicate conditions from which crystal were harvested and mounted for diffraction experiments. Green cells indicate conditions under which diffracting crystals were obtained.\n\nSix different conditions led to well-diffracting crystals (Figure 4). For these, data sets with resolutions between 2 and 1.3 Å could be collected. For the best diffracting crystal, the crystal structure was determined using a homology model created based on Vibrio cholerae FabB (VcFabB PDB Id 4XOX) as search model (Table 2). The crystal was in the space group C 2 2 21 and contained 2 protein molecules in the asymmetric unit.\n\nValues in parentheses are for the highest resolution shell.\n\nPaFabB C161A has the same overall fold as observed before for FabB and FabF from other organisms (Figure 5 and Figure 6A). The rmsd between PaFabB C161A and VcFabB (the protein with the highest sequence identity in the PDB (72%), PDB Id 4XOX) is 0.424 Å while the rmsd to the w.t. PaFabF (sequence identity 41%, PDB Id 4JPF) is 0.843 Å. The two catalytic histidines, His 296 and His 331, are highly conserved and well aligned with the catalytic histidines from both VcFabB as well as the ones from PaFabF (Figure 6B).\n\nBeta sheets and alpha helices are shown in yellow and red colour respectively while loops are shown in green.\n\nA) The three different enzymes are shown in orange, green and magenta cartoon style, respectively. B) Alignment of the active site catalytic triad of VcFabB, w. t. PaFabF and PaFabB C161A.\n\nDue to the high concentration of ethylene glycol (20% v/v) and salt in the well and protein buffers, respectively (150 mM NaCl and 200 mM NaI), 18 ethylene glycol molecules and 11 ions (Cl- and I-) were identified and placed in the crystal structure of PaFabB C161A during refinement (Figure 7A). Some of these molecules were found to bind in the active site of the protein (Figure 7B). The chloride ion Cl 1 binds tightly (B factor for Cl 1 is 18 Å2, average B-factor for protein atoms is 16.8 Å2, average ions B factors is 30.7 Å2) in the active site of chain B, in close proximity to the catalytic residues His 296 (3.3 Å) and His 331 (3. 2Å). Moreover, Cl 1 forms two additional interactions with an ethylene glycol (EDO511, average B factor 18 Å2) and a water molecule (HOH227) in the active site.\n\nA) The structure of PaFabB is shown as magenta cartoon style. Iodine and chloride ions are shown with deep purple and green colour respectively. B) Active site residues are shown as magenta sticks, water molecules and chloride ions are shown as red and green spheres, respectively, while the distances between the chloride ion Cl 1 and the neighbouring molecules are shown as yellow dashed lines.\n\nPhe 400/391 (numbering based on PaFabF/PaFabB) was previously identified, as one of the highly conserved active site residues, to play a pivotal role in substrate specificity and ligand binding, by adopting a different conformation between the w.t. and the intermediate state of the FabF enzyme.9,12 In w. t. PaFabF (PDB Id 4JPF, Figure 8A and B), Phe400 is in a ‘closed’ conformation (dihedral angle C-CA-CB-CG = -177.1o). When mutating the catalytic residue Cys 164 to Gln 164 (PDB Id 7OC1 – Figure 8A and C) the enzyme has been shown to mimic the intermediate state and to trap the Phe 391 into the ‘open’ conformation (dihedral angle C-CA-CB-CG = 168.8o). Here, the catalytic residue Cys 161 of PaFabB was mutated to Ala 161. As can be seen from the crystal structure (Figure 8A and D), Phe 391 adopts the ‘open’ conformation as expected for an intermediate-mimicking FabB variant (dihedral angle C-CA-CB-CG = 170.2o). Although, the overall sequence identity between PaFabB and PaFabF is only 41%, the conservation in the active site is much higher (Figure 9). Apart from Thr 271 in FabF that is mutated to Val 268 in FabB, all active site residues involved in hydrogen-bond interactions with platensimycin are conserved between the two enzymes (Figure 8A). That makes it highly likely that ligands binding into the active site of FabF may also bind to FabB with a similar affinity, and thus opens up the possibility for the designing of dual inhibitors for both FabF and FabB that will lead to a complete inhibition of the last step of the fatty acid elongation cycle.\n\nA) The active site residues of the three different enzymes are shown as green, cyan and magenta sticks, respectively. Platensimycin binding to PaFabF C164Q (PDB Id 7OC1) is shown as yellow sticks. Side chain conformation and dihedral angle C-CA-CB-CG of Phe391/400 is shown in B) for PaFabF C) for PaFabF C164Q and D) for PaFabB C161A.\n\nA) Alignment between chain A of PaFabF and PaFabB C161A is shown as cartoon style and color-coded based on the sequence identity between the two isoenzymes. B) Zoom in showing the active site and active site residues. Residue labels and numbering are based on PaFabB only.\n\n\nDiscussion\n\nIn this study, the first high-resolution crystal structure of PaFabB C161A is reported. This structure can now serve as a template for the structure-based design of FabB inhibitors. The C161A mutation of FabB in this crystal structure causes Phe 391 to be in the ‘open’ conformation (Figure 8) and allows targeting of the intermediate-acylated state of FabB; in a similar manner to the natural antibiotic platensimycin. Furthermore, due to the high conservation of the overall fold and the high sequence identity in the active site between the structure reported here with PaFabF C164Q (PDB Id 7OC1), both structures can be used as a template for the design of novel dual FabF/B inhibitors.\n\n\nMethods\n\nThe gene coding for P. aeruginosa PA14 FabB (ORF number (open reading frame): PA14_43690), with a single point mutation C161A was synthesised and cloned in a bacterial plasmid pET-28a(+)-TEV vector using the cloning sites NdeI/BamHI by Genscript. The plasmid had a DNA sequence coding for a 6-His-tag followed by a TEV cleavage site before PaFabB. Seven different E. coli strains (OverExpress C41(DE3) SOLOs and C43(DE3) SOLOs from Biosearch technologies; BL-21(DE3), BL-21(DE3) pLysS, C41(DE3) pLysS and C43(DE3) pLysS from Lucigen, and Rosetta (DE3) pLysS from Merck) were heat-shock transformed with the synthesised plasmid. Expression of PaFabB in each transformed cell line was tested as per manufacturer protocol.\n\nE.coli Rosetta (DE3) pLysS competent cells yielded the highest protein expression, based on SDS-PAGE analysis, and were used as an expression system for large-scale protein production and purification. Transformed cells were inoculated in 50 mL of LB medium supplemented with kanamycin (30 μg/mL) and chloramphenicol (50 μg/mL) overnight at 310 K. Pre-culture stocks were prepared by mixing the overnight culture with glycerol (final concentration 40% v/v), aliquoted and kept in –80 °C until use. For large-scale expression, 0.1 mL of pre-culture stock was inoculated in 100 mL of LB medium supplemented with kanamycin (30 μg/mL) and chloramphenicol (50 μg/mL) overnight at 310 K. The entire volume was then transferred into 900 mL of LB-medium containing antibiotics and the cell growth continued until OD600 reached 0.7. Protein expression was then induced by adding IPTG to a final concentration of 1 mM and the expression continued for another 3-3.5 hours.\n\nCells were harvested by centrifugation (15 minutes, 5000 g, 277 K), resuspended in lysis buffer (20 mM Tris-HCl, 500 mM NaCl, 20 mM imidazole, 1 mM DTT, 10% glycerol (v/v), pH 7.4) with addition of one tablet of Complete EDTA-free protease inhibitor cocktail (Roche) and incubated with magnet stirring for 60 minutes at 277 K. 20 U (units) of DNAse I (Sigma Aldrich) was added per cell pellet, before the mixture was sonicated on ice by an ultrasonic processor (Sonics, Vibra-Cell VC130) for a total of two minutes with 10 seconds pulses with amplitude 70. The debris and insoluble protein were pelleted by centrifugation at 15000 rpm, 277 K, for 30 minutes. The supernatant was collected and filtered with Whatman filter units 0.2 μM (GE healthcare) using a syringe. The protein was then purified using a Ni2+ Sepharose High Performance HisTrap HP 5 mL column (GE Healthcare) with an increasing imidazole gradient from 0 to 500 mM. The fractions containing PaFabB C161A were pooled and TEV protease was added to remove the affinity tag. The mixture was dialyzed with buffer (25 mM Tris–HCl pH 7.5, 150 mM NaCl) overnight at 277 K and the cleaved protein was purified by passage through a Ni2+ HisTrap column. SEC was then performed on a HiLoad 26/600 Superdex 75 pg column (Cytiva) with equilibration buffer (20 mM Tris-HCl, 150 mM NaCl, 1 mM DTT, pH 7.4). Purity was confirmed by SDS–PAGE (Mini-PROTEAN TGX Stain-Free Precast Gel; Bio-Rad) and the final concentration of PaFabB C161A was determined using a NanoDrop ND-1000 (Thermo Fisher Scientific).\n\nFor crystallization trials JCSG+ (MD1-37), PACT premier (MD1-29) and LFS (Ligand Friendly Screen, MD1-122) crystallization screens from Molecular Dimensions were used. His-tag cleaved PaFabB C161A (23 mg/mL) in 20 mM Tris-HCl, 150 mM NaCl, 1 mM DTT, pH 7.4, was mixed with well buffer in different ratios (2:1, 1:1 and 1:2) on a Triple Sitting Drop 96-well plate (TTP Labtech) using a crystallography Mosquito LCP (TTP LabTech). The plates were incubated at 20°C. Optimization (Figure 4) of the initial hit conditions (Table 2) was achieved by varying the precipitants and protein concentrations while keeping the salt and buffer concentration constant. Optimisation led to rod-shaped crystals (250 × 100 × 10 μm) in multiple drops (Figure 3).\n\nCrystals with a final concentration of precipitant lower than 25%(w/v) were cryoprotected with a mixture consisting of the crystallization buffer and Cryomix 9 from CryoSol MD1-90 (Molecular Dimensions) (final composition of the cryomixture: 0.2 M NaI, 0.1 M Bis-Tris propane pH 7.5, 5%(w/v) PEG 3350, 10% (v/v) EG 5 % (v/v), diethylene glycol, 5 % (v/v) 1,2-propanediol, 5 % (v/v) dimethyl sulfoxide, 5 % (v/v) glycerol, 5 mM NDSB 201 (3-(1-Pyridinio)-1-propanesulfonate), 5 % (v/v) 1,4-dioxane) prior to flash-cooling in liquid nitrogen.\n\nX-ray data were collected from single crystals at the DESY synchrotron (Hamburg, Germany) at the P11 high-throughput MX beamline. In each case, crystals were maintained at 100 K and the X-ray wavelength was 0.976246 Å. Data were processed with the automatic data processing pipeline of P11 beamline, using XDS.13\n\nThe structure was solved by molecular replacement using Dimple14 from the CCP4i2 suite.15 As search model, a homology model generated from wt. VcFabB (PDB Id 4XOX) with 72% sequence identity was used. Refinement was performed using REFMAC516 while inspection of electron-density and difference density maps and model manipulation was achieved using Coot.17 During refinement, water molecules, ions and side-chain conformers were included. The model geometry was assessed using MolProbity,18 the PDB redo server19 and the PDB validation tools. The crystallographic data and refinement statistics are listed in Table 2. The figures were generated with PyMOL v.2.4.1 (Schrödinger, LLC) and VMD v.1.9.3.20\n\n\nData availability\n\nProtein Data Bank: The crystal structure of PaFabB C161A with the PDB Id 7PPS, https://doi.org/10.2210/pdb7PPS/pdb.21",
"appendix": "Acknowledgements\n\nWe acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at PETRA III and we would like to thank Johanna Hakanpää and Sofiane Saouane for assistance in using the P11 beamline. Beamtime was allocated for the proposal BAG-20190768 EC. We thank Khan Kim Dao for excellent support with protein purification and Ludvik Olai Espeland for help with preparing Figure 1.\n\n\nReferences\n\nBrown ED, Wright GD: Antibacterial Drug Discovery in the Resistance Era. Nature. 2016; 529(7586): 336–343. PubMed Abstract | Publisher Full Text\n\nO’Neill J: Review on Antimicrobial Resistance. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations.2016. Reference Source.\n\nYao J, Rock CO: Bacterial Fatty Acid Metabolism in Modern Antibiotic Discovery. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2017; 1862(11): 1300–1309. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPoulsen BE, Yang R, Clatworthy AE, et al.: Defining the Core Essential Genome of Pseudomonas Aeruginosa. PNAS. 2019; 116(20): 10072–10080. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTurner KH, Wessel AK, Palmer GC, et al.: Essential Genome of Pseudomonas Aeruginosa in Cystic Fibrosis Sputum. PNAS. 2015; 112(13): 4110–4115. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee SA, Gallagher LA, Thongdee M, et al.: General and Condition-Specific Essential Functions of Pseudomonas Aeruginosa. PNAS. 2015; 112(16): 5189–5194. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSkurnik D, Roux D, Aschard H, et al.: A Comprehensive Analysis of in vitro and in vivo Genetic Fitness of Pseudomonas Aeruginosa Using High-Throughput Sequencing of Transposon Libraries. PLoS Pathog. 2013; 9(9): e1003582. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiberati NT, Urbach JM, Miyata S, et al.: An Ordered, Nonredundant Library of Pseudomonas Aeruginosa Strain PA14 Transposon Insertion Mutants. PNAS. 2006; 103(8): 2833–2838. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang J, Soisson SM, Young K, et al.: Platensimycin Is a Selective FabF Inhibitor with Potent Antibiotic Properties. Nature. 2006; 441(7091): 358–361. PubMed Abstract | Publisher Full Text\n\nWang J, Kodali S, Lee SH, et al.: Discovery of Platencin, a Dual FabF and FabH Inhibitor with in vivo Antibiotic Properties. PNAS. 2007; 104(18): 7612–7616. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSingh SB, Ondeyka JG, Herath KB, et al.: Isolation, Enzyme-Bound Structure and Antibacterial Activity of Platencin A1 from Streptomyces Platensis. Bioorg. Med. Chem. Lett. 2009; 19(16): 4756–4759. PubMed Abstract | Publisher Full Text\n\nBaum B, Lecker LSM, Zoltner M, et al.: Structures of Pseudomonas Aeruginosa β-Ketoacyl-(Acyl-Carrier-Protein) Synthase II (FabF) and a C164Q Mutant Provide Templates for Antibacterial Drug Discovery. Acta Crystallogr. F: Struct. Biol. Commun. 2015; 71(8): 1020–1026. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKabsch W: XDS. Acta Crystallogr. D Biol. Crystallogr. 2010; 66(Pt 2): 125–132. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWojdyr M, Keegan R, Winter G, et al.: DIMPLE - a Pipeline for the Rapid Generation of Difference Maps from Protein Crystals with Putatively Bound Ligands. Acta Crystallogr. A. 2013; 69(a1): s299. Publisher Full Text\n\nPotterton L, Agirre J, Ballard C, et al.: CCP4i2: The New Graphical User Interface to the CCP4 Program Suite. Acta Crystallogr D Struct Biol. 2018; 74(Pt 2): 68–84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMurshudov GN, Skubák P, Lebedev AA, et al.: REFMAC5 for the Refinement of Macromolecular Crystal Structures. Acta Cryst D. 2011; 67(4): 355–367. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEmsley P, Cowtan K: Coot: Model-Building Tools for Molecular Graphics. Acta Crystallogr. D Biol. Crystallogr. 2004; 60(Pt 12 Pt 1): 2126–2132. Publisher Full Text\n\nWilliams CJ, Headd JJ, Moriarty NW, et al.: MolProbity: More and Better Reference Data for Improved All-Atom Structure Validation. Protein Sci. 2018; 27(1): 293–315. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoosten RP, Long F, Murshudov GN, et al.: The PDB_REDO Server for Macromolecular Structure Model Optimization. IUCrJ. 2014; 1(Pt 4): 213–220. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHumphrey W, Dalke A, Schulten K: VMD: Visual Molecular Dynamics. J. Mol. Graph. 1996; 14(1): 33–38. PubMed Abstract | Publisher Full Text\n\nGeorgiou C, Brenk R, Yadrykhinsky V: Announcing the worldwide Protein Data Bank. Nat. Struct. Biol. 2003; 10: 980. Publisher Full Text"
}
|
[
{
"id": "98455",
"date": "15 Nov 2021",
"name": "Bjarte A. Lund",
"expertise": [
"Reviewer Expertise Biochemistry",
"structural biology",
"enzymology"
],
"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\nYadrykhins'ky et al. present an interesting story on the exploration of a new system for the development of new antibiotics. The authors make a convincing case for why fatty acid synthesis is a good target. Furthermore, the authors convey a clear technical step towards the goal by engineering a mutant variant of one enzyme in the pathway which mimics the intermediate step of the enzymatic reaction. An intermediate state that has been found to be susceptible to other inhibitors.\nMy objections to this paper are not on the technical and scientific soundness of the work but on its presentation.\n\nThe introduction is short and does not clearly convey to me as a non-expert how the mutation of a Cys to Gln/Ala would make the enzyme resemble the intermediate state. I need to read all the way until Figure 9 and the Discussion to be informed about the Phe-residue that flips between open/closed conformations.\n\nAfter reading the paper, it is still not clear to me whether Gln was tried, or whether other amino acids could have had the same effect. Perhaps it is not important since Ala apparently worked.\n\nIn the Abstract, acyl-intermediate could more clearly be written as acyl-enzyme intermediate.\n\nResults, Protein expression, and purification, TEV site would more precisely be termed TEV protease cleavage site.\n\nResults, Crystallization (Figure 2) C164A/C161A is mixed non-consistently. I can only assume this is a mix-up with the group's other work with FabF. But it is very confusing to the reader.\n\nClearly out of scope to the paper, but it would have been interesting to know if iodine-phasing was tested.\n\nIt is unclear how the resolution cutoff was decided. I/sig(I) is still very high at the highest resolution shell. It would also have been useful if CC* or CC1/2 was presented in Table 2.\n\nThe very short Discussion-segment could have been merged with the Results-section. The discussion does raise the very interesting possibility of dual-target inhibitors that would presumably be of high interest with regards to the emergence of resistance. This could have been emphasized earlier as well.\n\nMethods, The sonication amplitude appears to lack a unit, presumably %. For the protein concentration determination, the extinction coefficient used should be given.\n\nReference 21 appears to be a mistake.\n\nAll in all, I did appreciate the work and look forward to the continuation of the story.\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": "7615",
"date": "10 Jan 2022",
"name": "Ruth Brenk",
"role": "Author Response",
"response": "Thank you Bjarte for reviewing our article! Here follows a point-to-point reply to the issues that you have raised. The introduction is short and does not clearly convey to me as a non-expert how the mutation of a Cys to Gln/Ala would make the enzyme resemble the intermediate state. I need to read all the way until Figure 9 and the Discussion to be informed about the Phe-residue that flips between open/closed conformations. We have added a new Figure (now Figure 2) together with some explanatory text in the introduction to make this clearer. After reading the paper, it is still not clear to me whether Gln was tried, or whether other amino acids could have had the same effect. Perhaps it is not important since Ala apparently worked. We have initially tried the Gln variant, but because this was less stable, we decided to work with the Ala variant instead. We have added this explanation to the end of the introduction. In the Abstract, acyl-intermediate could more clearly be written as acyl-enzyme intermediate. Done. Results, Protein expression, and purification, TEV site would more precisely be termed TEV protease cleavage site. Done. Results, Crystallization (Figure 2) C164A/C161A is mixed non-consistently. I can only assume this is a mix-up with the group's other work with FabF. But it is very confusing to the reader. This was indeed a mix-up with the number from FabF which has now been corrected (figure legend for what is now Figure 3). Clearly out of scope to the paper, but it would have been interesting to know if iodine-phasing was tested. We agree that this would be interesting, but we have not yet tested this. We might try it in the future. It is unclear how the resolution cutoff was decided. I/sig(I) is still very high at the highest resolution shell. It would also have been useful if CC* or CC1/2 was presented in Table 2 The resolution was limited by the distance of the detector. Unfortunately, we had major problems with shipping crystals to the synchrotron this spring and lost two consecutive shipments due to shipping/custom problems. As the work presented in this paper is from a master thesis, there was no time to repeat the measurements, but it looks like the crystals might diffract even beyond 1.3 Å. We have added CC1/2 to Table 2. The very short Discussion-segment could have been merged with the Results-section. The discussion does raise the very interesting possibility of dual-target inhibitors that would presumably be of high interest with regards to the emergence of resistance. This could have been emphasized earlier as well. We have renamed the Results section to Results and Discussion and the old Discussion section to Conclusions. The discussion about dual-target inhibitors for both, the malonyl-CoA binding site and the fatty acid channel (see comments from Klaus Reuter) has been added to what is now the Results and Discussion section. Methods, The sonication amplitude appears to lack a unit, presumably %. For the protein concentration determination, the extinction coefficient used should be given. Done Reference 21 appears to be a mistake. Deleted. We hope that we have answered to all issues that you have raised to your full satisfaction. If not, please let us know what else we should address."
}
]
},
{
"id": "101462",
"date": "06 Dec 2021",
"name": "Klaus Reuter",
"expertise": [
"Reviewer Expertise protein crystallography",
"enzymology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirst of all: Apart from the fact that I do not insist on CC* or CC1/2 values in Table 2, I do absolutely agree with every single concern of the 1st reviewer making it unnecessary to restate all these points.\nFurther (minor) issues:\nPage 3, Introduction, 1st paragraph, line 3: Replace “drug-resistant infections” with “infections caused by drug-resistant pathogens”.\n\nPage 3, Introduction, 2nd paragraph, line 4: Replace “w.t. enzyme” with “apo-enzyme”.\n\nPage 3, Figure 1 (B): In the first partial reaction of the FabF/B-catalysed reaction, the authors indicate the incoming HS-FabF/B (above the reaction arrow) but forget to indicate the leaving HS-ACP.\n\nPage 4, Results/Protein expression and purification, 2nd paragraph, line 2: Replace “… FabB with a cleaved His-tag …” with“… FabB lacking the His-tag …”.\n\nPage 4, Results/Crystallization of PaFabB C161A, 1st paragraph, line 2: Replace “cleaved FabB” with “FabB lacking the His-tag”.\n\nPage 5, Results/Crystal structure of PaFabB C161A, 1st paragraph, line 3: rmsd values for superimposed structures are given with three significant digits, respectively, which suggests inappropriately high accuracy. 0.424 Å should be replaced by 0.42 Å and 0.843 Å by 0.84 Å.\n\nPage 5, Results/Crystal structure of PaFabB C161A, 1st paragraph, line 5: Replace “… from both VcFabB as well as the ones from PaFabB …” with“… from both VcFabB and PaFabB …”.\n\nPage 6, Results/Active site and differences to PaFabF, 1st paragraph, line 1: The 1st sentence of this paragraph has to be reformulated. It does not make sense in its present form.\n\nPage 7, Table 2: Again, several values are given with inappropriately high accuracy. Multiplicity: 6.84 (6.56) should be replaced by 6.8 (6.6); I/sig(I): 19.11 (3.45) should be replaced by 19.1 (3.5); Ramachandran plot, residues in (%): (96.02%) should be replaced by (96.0%) and (3.98%) by (4.0%).\n\nPage 8, Results/Active site and differences to PaFabF, 1st paragraph, line 1: Replace “w.t.” with “apo-”.\n\nPage 8, Results/Active site and differences to PaFabF, 1st paragraph, line 2: Replace “When mutating …” with “Upon the mutation of …”.\n\nPage 8, Results/Active site and differences to PaFabF, 1st paragraph, line 8: Replace “… is mutated to Val268 …” with “… is replaced by Val268 …” or “… corresponds to Val268 …”.\n\nFigure 5: It is not immediately obvious if the figure shows the homodimer or a single subunit only. This information should be given. If the complete dimer is shown (which I presume) it would make sense to present its subunits in different colours or shades of colour. The same applies to subsequent figures.\n\nMajor concern:\nThe many figures showing FabB or the superpositions of different FabB/F enzymes are not very meaningful. FabB and FabF differ in substrate specificity for the fatty acid chain. The authors should definitely discuss the reasons for the respective substrate specificity by means of available structures.\n\nI wish the authors had explained why the C161A mutation leads to the open conformation of the active site (see reviewer 1).\n\nIn summary, the manuscript is scientifically sound and significant, although somewhat greater effort should have been put into its presentation.\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": "7617",
"date": "10 Jan 2022",
"name": "Ruth Brenk",
"role": "Author Response",
"response": "Thank you Klaus for reviewing our paper and for very constructive feedback! Below follows a point-to-point reply to all issues that you have raised. First of all: Apart from the fact that I do not insist on CC* or CC1/2 values in Table 2, I do absolutely agree with every single concern of the 1st reviewer making it unnecessary to restate all these points. We have addressed all points that Bjarte Lund has raised. Please refer to the reply to his comments to see what we have changed. Page 3, Introduction, 1st paragraph, line 3: Replace “drug-resistant infections” with “infections caused by drug-resistant pathogens”. Done Page 3, Introduction, 2nd paragraph, line 4: Replace “w.t. enzyme” with “apo-enzyme”. Done Page 3, Figure 1 (B): In the first partial reaction of the FabF/B-catalysed reaction, the authors indicate the incoming HS-FabF/B (above the reaction arrow) but forget to indicate the leaving HS-ACP. Corrected as suggested Page 4, Results/Protein expression and purification, 2nd paragraph, line 2: Replace “… FabB with a cleaved His-tag …” with“… FabB lacking the His-tag …”. Done Page 4, Results/Crystallization of PaFabB C161A, 1st paragraph, line 2: Replace “cleaved FabB” with “FabB lacking the His-tag”. Done Page 5, Results/Crystal structure of PaFabB C161A, 1st paragraph, line 3: rmsd values for superimposed structures are given with three significant digits, respectively, which suggests inappropriately high accuracy. 0.424 Å should be replaced by 0.42 Å and 0.843 Å by 0.84 Å. Done Page 5, Results/Crystal structure of PaFabB C161A, 1st paragraph, line 5: Replace “… from both VcFabB as well as the ones from PaFabB …” with“… from both VcFabB and PaFabB …”. Done Page 6, Results/Active site and differences to PaFabF, 1st paragraph, line 1: The 1st sentence of this paragraph has to be reformulated. It does not make sense in its present form. This sentence reads now: “The highly conserved Phe400/391 (numbering based on PaFabF/PaFabB) in the malonyl-CoA binding site was previously identified to play a pivotal role in substrate specificity and ligand binding, as this residue adopts different conformations in the apo and the intermediate-binding state.” Page 7, Table 2: Again, several values are given with inappropriately high accuracy. Multiplicity: 6.84 (6.56) should be replaced by 6.8 (6.6); I/sig(I): 19.11 (3.45) should be replaced by 19.1 (3.5); Ramachandran plot, residues in (%): (96.02%) should be replaced by (96.0%) and (3.98%) by (4.0%). Done Page 8, Results/Active site and differences to PaFabF, 1st paragraph, line 1: Replace “w.t.” with “apo-”. Done Page 8, Results/Active site and differences to PaFabF, 1st paragraph, line 2: Replace “When mutating …” with “Upon the mutation of …”. Done Page 8, Results/Active site and differences to PaFabF, 1st paragraph, line 8: Replace “… is mutated to Val268 …” with “… is replaced by Val268 …” or “… corresponds to Val268 …”. Done Figure 5: It is not immediately obvious if the figure shows the homodimer or a single subunit only. This information should be given. If the complete dimer is shown (which I presume) it would make sense to present its subunits in different colours or shades of colour. The same applies to subsequent figures. We have added the information to the relevant figures (now 6 and 7) and colored the subunits as suggested. The many figures showing FabB or the superpositions of different FabB/F enzymes are not very meaningful. FabB and FabF differ in substrate specificity for the fatty acid chain. The authors should definitely discuss the reasons for the respective substrate specificity by means of available structures. We have inserted a new section to discuss the substrate selectivity with respect to fatty acids “Comparison of fatty acid chain binding channel in and in PaFabB and PaFabF”. In addition, we have deleted the old Figure 5. I wish the authors had explained why the C161A mutation leads to the open conformation of the active site (see reviewer 1). An explanation has been added to what is now the second paragraph in the section “Comparison of malonyl-CoA binding sites in PaFabB and PaFabF”. We hope that we have answered all issues that you have raised to your full satisfaction. If not, please let us know what else we should modify."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1102
|
https://f1000research.com/articles/10-573/v1
|
15 Jul 21
|
{
"type": "Systematic Review",
"title": "Lateral versus posterior surgical approach for the treatment of supracondylar humeral fractures in children: a systematic review and meta-analysis",
"authors": [
"Komang Agung Irianto",
"I Putu Gede Pradnyadewa Pradana",
"Brigita De Vega",
"I Putu Gede Pradnyadewa Pradana",
"Brigita De Vega"
],
"abstract": "Background: Supracondylar humeral fracture (SHF) is the most common type of fracture in children. Moreover, lateral and posterior surgical approaches are the most frequently chosen approaches for open reduction surgery in displaced SHF when closed reduction fails. However, previous literature showed mixed findings regarding functional and cosmetic outcomes. Currently, no systematic review and meta-analysis has compared these two procedures. Methods: Our protocol was registered at PROSPERO (registration number CRD42021213763). We conducted a comprehensive electronic database search in MEDLINE, EMBASE, and CENTRAL. Two independent reviewers screened the title and abstract, followed by full-text reading and study selection based on eligibility criteria. The quality of the selected studies was analyzed with the ROBINS-I tool. Meta-analysis was carried out to compare the range of motion (functional outcome) and cosmetic outcome according to Flynn’s criteria. This systematic review was conducted based on PRISMA and Cochrane handbook guidelines. Results: Our initial search yielded 163 studies, from which we included five comparative studies comprising 231 children in the qualitative and quantitative analysis. The lateral approach was more likely to result in excellent (OR 1.69, 95% CI [0.97-2.93]) and good (OR 1.12, 95% CI [0.61-2.04]) functional outcomes and less likely to result in fair (OR 0.84, 95% CI [0.34-2.13]) and poor (OR 0.42, 95% CI [0.1-1.73]) functional outcomes compared to the posterior approach. In terms of cosmetic results, both approaches showed mixed findings. The lateral approach was more likely to result in excellent (OR 1.11, 95% CI [0.61-2.02]) and fair (OR 1.18, 95% CI [0.49-2.80]) but less likely to result in good (OR 0.79, 95% CI [0.40-1.55]) cosmetic outcomes. However, none of these analyses were statistically significant (p> 0.05). Conclusion: Lateral and posterior surgical approaches resulted in satisfactory functional and cosmetic outcomes. The two approaches are comparable for treating SHF in children when evaluated with Flynn’s criteria.",
"keywords": [
"supracondylar fractures",
"humeral fractures",
"lateral approach",
"posterior approach",
"children"
],
"content": "Introduction\n\nSupracondylar humeral fracture (SHF) is an elbow injury in children that most often requires surgical therapy. Nearly 60-70% of all elbow injuries occur in children aged five to seven.1 In the USA, it is reported that 25-40% of the incidence of SHF occurs in children's playgrounds.2 From all the injuries to the elbow joint that can occur in children, 85% occurs in the distal humerus area, and 55-75% of the total fractures of the distal humerus are fractures of the supracondylar humerus. The annual incidence of SHF in the US is estimated at 177.3 per 100,000 children. Moreover, the incidence of trauma as the leading cause of SHF has a seasonal distribution. The literature shows that SHF is more frequent in the summer and is more common in the left elbow or non-dominant limb.3 In addition, SHF may give rise to an emergency, namely compartment syndrome. This life and limb-threatening complication occurs in 0.3-1% of all SHF cases. A study conducted by Houshian et al. shows that elbow fracture incident is 308/100,000 per year; supracondylar humeral fracture comprises 58% of all incidents.4,5\n\nTreatment choices for SHF in children can be classified into non-operative and operative treatment. In cases where the fracture configuration is not displaced (Gartland type 1) or minimally displaced (Gartland type 2), the primary treatment choice is non-operative. Whereas, in displaced fractures (Gartland type 3 or 4), the first option is operative treatment with closed reduction techniques and percutaneous Kirschner wire insertion. However, when these attempts fail, the next step is to perform an open reduction and internal fixation (ORIF) to obtain an optimal reduction. Anatomical restoration of displaced fractures is important since it will affect the outcome on the function of the elbow joint.6,7\n\nThere are various surgical approaches in open reduction surgery for SHF. Several approaches that are commonly used are lateral, medial, and posterior approaches. As they can only provide visualization to some part of the fracture site, a combination of them is often performed. These three operating approaches can include fairly straightforward operating approaches. A lateral approach is often used because this approach causes relatively less destruction to important neurovascular structures and soft tissues but still gives enough exposure to reposition the fracture site. Sometimes, this approach can be combined with a medical approach if necessary, but that will add another scar and also extensive soft tissue exposure. Another approach that can be performed is the anterior approach, which possesses several advantages, one of which is evacuating the hematoma at the fracture site because usually, the hematoma will accumulate in the anterior side of the fracture site. However, the downside of the anterior approach is its challenging technique because there will be quite a number of neurovascular structures that require extra caution.8 Moreover, the posterior surgical approach is also often used due to its simplicity as it does not require much neurovascular structure identification, thus results in shorter surgery time.\n\nTo date, there is no definite consensus on which operating approach should be used as the main approach in open repositioning surgery for SHF treatment in children. Thus, it is our aim to carry out a comprehensive systematic review to determine the best surgical approach in SHF, especially comparing those that are often chosen, namely the posterior and lateral surgical approaches, in order to achieve the goal of high patient satisfaction.\n\n\nMethods\n\nWe followed PRISMA and Cochrane handbook guidelines for conducting a systematic review of interventions. Our protocol has been registered at PROSPERO (registration number CRD42021213763).\n\nThis research is a systematic review and meta-analysis that includes a direct comparative study between lateral and posterior surgical approaches for supracondylar humeral fractures (SHF) in children. We included original clinical studies which were written in English and available in full-text. However, we did not include the following types of articles: abstract conferences, letters to editors, summaries of meetings, expert opinions, book chapters, study protocols, technical reports, narrative reviews, systematic reviews, meta-analyses, case reports, studies with incomplete data, duplication of publications, experimental studies on animals, and cadavers, laboratory (in vitro), and computational studies.\n\nThe population used in this study were children diagnosed with supracondylar humeral fractures who underwent open reduction and internal fixation surgery using a lateral or posterior surgical approach. Patients who underwent conservative treatment or surgeries with other approaches were not included in this review. We also excluded the studies that used combined approaches. The primary outcome assessed in this study was functional and cosmetic outcomes according to Flynn's criteria9 (Table 1).\n\nWe conducted an electronic literature search in MEDLINE (from 1966 until 1 November 2020), EMBASE (from 1947 until 1 November 2020), and The Cochrane Central Register of Controlled Trials (CENTRAL) (from inception until 1 November 2020) using free-text keywords and subject subheading (Medical Subject Headings (MeSH) for MEDLINE and Emtree for EMBASE). Our search strategy can be seen in Extended Data.30 The PICO concept (Patient, Intervention, Comparison, Outcome) was used in conceptualizing this research strategy:\n\n• P: children diagnosed with supracondylar humeral fractures requiring open reduction and internal fixation surgeries,\n\n• I: open reduction and internal fixation with a lateral or posterior approach,\n\n• C: as explained in Intervention (I),\n\n• O: Fylnn’s criteria evaluation.\n\nStudy references obtained from the search were transferred to Mendeley software version 1.19.8 (Elsevier, United Kingdom) to detect duplicates. Two independent reviewers screened the references by title and abstract based on the eligibility criteria using Rayyan® webpage,10 and labelling was carried out using ‘include’, ‘maybe’, and ‘excluded features’. Potentially eligible studies or studies that remained unclear were included in the full-text reading. Any disagreement that arose was resolved by a third reviewer. Studies that were excluded at the full-text reading stage were recorded and provided with reasons. The flow of the study selection process is presented in the PRISMA flow diagram.\n\nThe selected studies were extracted using Microsoft Excel® software. We collected the following data: author, year of publication, title, type of study, patient demographics (sex, age), SHF classification, follow-up duration, surgical approach, functional and cosmetic outcome based on Flynn's criteria, and authors’ conclusions.\n\nBias analysis was carried out using the risk of bias tools formulated by the Cochrane group. For Randomized Controlled Trial (RCT) studies, we used the second version of the Cochrane tool, Risk of Bias (ROB).11 Potential causes of bias were assessed with signaling questions to detect biases caused by the randomization process, deviation from initial intervention intent, missing data, measurement of outcomes, and reporting of selective bias. For non-RCT studies, we used ROBINS-I (Risk of Bias in Non-randomized Studies of Intervention).12 The component of the assessment was the same as the measurement of bias using the ROB, but there were additional biases such as bias in patient selection and bias due to confounding factors. Meta-analyses were conducted only with studies that had a moderate or better risk of bias.\n\nWe assessed odds ratios (ORs) with a 95% confidence interval (CI) for the data. Heterogeneity (inconsistency) was analyzed using the Chi2 and I2 tests. A low p-value result (p < 0.1) of the Chi2 test indicates significant heterogeneity. Because the Chi2 test has a low detection ability in a small sample of data, we also used the I2 test to assess heterogeneity. An I2 test score of more than 50% has significant heterogeneity. Statistical analyses were performed using the Review Manager (RevMan)® version 5.3 (Nordic Cochrane Center, Denmark). If the heterogeneity test results showed no significant heterogeneity, we planned to use the fixed-effect models. Otherwise, the researchers used random-effect models to process the data. Subgroup analyses were also planned to explore the causes of high heterogeneity13 based on the type of study (RCT and non-RCT). When we encountered an unclear (inconclusive) decision, we carried out a sensitivity analysis test by repeating the meta-analysis with other effect magnitudes (risk ratio/RR, odds ratio/OR, and mean difference) and alternative statistical models (fixed and random effects models).12 To ensure a reliable meta-analysis result, we did not include studies that have a high risk of bias.\n\n\nResults\n\nOur initial electronic search results yielded 163 studies that matched the search keyword algorithm in the three major databases. The duplication removal process resulted in a total of 102 studies. The remaining studies were then screened by title and abstracts that had conformity to the inclusion and exclusion criteria. At this stage, we excluded 84 studies that were deemed irrelevant. The remaining 18 studies were then read as full-text articles to assess their suitability for this study. We excluded 13 studies due to several reasons: six studies were case series studies; three studies used a different operating approach from the main study; one study was an article review; one study was found to be not in accordance with the objectives of this study; one study was not supracondylar humeral fractures (different population); and one last study was not in English. Finally, five studies that were suitable for this review were chosen. A brief description of the study search is presented in Figure 1.\n\nThe five studies included were all retrospective, case-control studies conducted in Turkey,14–16 Thailand,17 and France18 between 2004 and 2013. The earliest study was initiated by Bamrungthin in 2004,17 while the latest study was conducted by Basaran et al.18 and Uzer et al.14 in 2010. The total number of patients in this study was 231 patients. One study15 did not specify the sex distribution of the patients. Of the five other studies included in this study, it was found that 119 patients (62%) were male, and 72 patients (38%) were female. All patients were children diagnosed with displaced supracondylar humeral fractures.\n\nAll patients in these studies had surgical management performed in the operating room using either a lateral or posterior operative approach to perform open repositioning of the fracture and then fixed with Kirschner wire to maintain the repositioning. After being operated on, the operated limb was supported with a back slab. All patients in this study were subjected to periodic examinations at the polyclinic for functional and cosmetic measurements using Flynn's criteria. The follow-up time in each study was different, ranging from 6-7 months18 until up to 50 months16 following the surgery.\n\nOverall, the five included studies had a moderate risk of bias. The summary of the risk of bias analysis using ROBINS-I tool can be seen in Table 2.\n\n• Confounding bias\n\nThis bias can arise if the interventions and outcomes have a different relationship from the cause due to confounding factors. Examples of common confounding factors are the presence of comorbid diseases and differences in socioeconomic status (including access to health insurance), which affect changes in the choice of intervention and changes in outcomes that are different from conditions in general.12,13 In this study, the authors found there was no risk of confounding factors.\n\n• Bias in the selection of research subjects\n\nThe author found there were two studies14,17 that had a low risk of bias in the selection of study subjects. In these studies, the researchers included all patients who met the inclusion criteria (patients with displaced supracondylar humeral fractures who were operated on with open reduction and percutaneous K-wire fixation posteriorly and laterally). Meanwhile, the other three studies15,16,18 had moderate bias because, despite the well-described inclusion criteria and subject selection flow, the number and reasons for exclusion of some subjects were not well defined.12,13 Therefore, the authors judged the possibility of bias in the selection of research subjects in these four studies.\n\n• Bias in the classification of the intervention group\n\nBias in the classification of the intervention group is low if the definition of the intervention is well explained and the definition of the intervention is only based on the information gathered at the time of the intervention (not determined later).12,13 The authors assigned a low degree of bias to this category because all studies adequately explained the definition and operational approach of the two intervention groups. Additionally, the definition of the intervention was taken at the time the operation was performed (recorded in the operation log), thereby reducing the risk of bias. Therefore, the authors found no bias in misclassifying the intervention group.\n\n• Bias due to deviations from previously planned interventions\n\nDeviations from previously planned interventions can occur when the patient does not adhere to the prescribed intervention or when the patient can change/switch intervention groups during the study period (in other words, there is a protocol violation).12,13 The authors considered this bias as not having sufficient information because all studies included in this study were retrospective studies of medical records, and there was no predetermined protocol. Therefore, it was quite difficult to judge whether there was a protocol violation or not.\n\n• Bias due to missing/incomplete data\n\nThis type of bias occurs when a large number of patients experiences loss of follow-up after they are included in the study (90-95% data availability is deemed sufficient), or when participants are excluded from the analysis by the principal investigator without clear justification/reasons.12,13 The study conducted by Turkmen et al.16 was considered to have a moderate bias due to incomplete data. Investigators in this study noted that they excluded a number of patients due to incomplete data or loss to follow-up but did not adequately explain the numbers. The other four studies15,16,18,19 were considered to have a low bias because all the required data were presented in full.\n\n• Bias in outcome measures\n\nBias in the measurement of results is categorized as low if it meets the following criteria: (i) the method of measuring the results used by all groups is equal and equivalent; (ii) the measurement of the results is objective (cannot be influenced by the knowledge of the type of intervention received by the research subject) or the outcome assessor does not know the type of intervention received by the research subject; and (iii) the existence of an error in measuring the results is not related to the intervention.12,13 The authors considered the five studies as having low bias because they met all of the above criteria.\n\n• Bias in the selection of reported results\n\nThe authors found that all studies included in this study had a moderate bias in the selection of reported results. This bias was assessed by matching the results of reports or scientific articles published in peer-reviewed journals with the protocols registered before the study was conducted (for example, registering clinical studies on clinicaltrial.gov).12,13 Since all five studies are retrospective, there will always be a bias in this category. However, the risk of bias was categorized as moderate (not serious/high risk) because, in the methodology section, all studies clearly explained the method of measurement and statistical analysis used.\n\nThe patient demographic and surgery outcomes of the included studies are presented in Tables 3 and 4.\n\nL: Lateral surgical approach, P: Posterior surgical approach, NI: No information.\n\nL: Lateral surgical approach, P: Posterior surgical approach.\n\nFlynn’s criteria divides the results of the evaluation into two major groups: satisfactory and unsatisfactory. The summary of the lateral surgical approach outcomes from the included studies is presented in Figure 2. Overall, the lateral surgical approach resulted in 98% functional satisfaction and 99% cosmetic satisfaction. Meanwhile, the posterior surgical approach resulted in 94% functional satisfaction and 99% cosmetic satisfaction (Figure 3).\n\nMeta-analyses were conducted to quantify the difference between the two surgical approaches. We divided the meta-analyses based on the subgroup grading of Flynn’s criteria (excellent, good, fair, poor). Overall, all of the data included in the meta-analyses had low heterogeneity (I2 < 50%), which means that our data were consistent.\n\nFunctional outcome\n\nFigure 4 shows the functional outcome of the meta-analysis in the excellent subgroup, while Figure 5 shows the meta-analysis’ functional outcome in the good subgroup. The lateral approach was 69% (OR 1.69, 95% CI [0.97-2.93]) and 12% (OR 1.12, 95% CI [0.61-2.04]) more likely to result in excellent and good results, respectively, compared to the posterior approach. However, these differences were not statistically significant (p = 0.06 and p = 0.72, respectively).\n\nMoreover, the lateral approach resulted in lower fair and poor results by 16% (OR 0.84, 95% CI [0.34-2.13]) and 58% (OR 0.42, 95% CI [0.10-1.73]), respectively, compared to the posterior approach (Figure 6 and Figure 7). However, these differences were not statistically significant (p = 0.72 and p = 0.23, respectively).\n\nCosmetic outcome\n\nIn terms of cosmetic results, both approaches showed mixed findings. The lateral approach was more likely to result in excellent (OR 1.11, 95% CI [0.61-2.02]) but less likely to result in good (OR 0.79, 95% CI [0.40-1.55]) cosmetic outcomes compared to the posterior approach (Figure 8 and Figure 9). Interestingly, the lateral approach was also more likely to result in a fair (OR 1.18, 95% CI [0.49-2.80]) cosmetic outcome than the posterior approach (Figure 10). However, none of these findings were statistically significant (p = 0.73, p = 0.49, and p = 0.71, respectively). In other words, the cosmetic outcome was relatively comparable amongst the two approaches. We did not perform a meta-analysis for the poor subgroup as only one study17 reported the poor outcome; thus, it could not be compared.\n\n\nDiscussion\n\nSupracondylar humeral fracture (SHF) is a type of elbow injury in children that most often requires operative therapy than other injuries. 60 to 70% of all elbow injuries in children occur between five and seven years of age.1 The SHF types that often require ORIF are those that fall into Gartland classification type 3 or 4. There is a shift from the fracture location in these types, making the configuration very unstable. Moreover, the unsuccessful reduction of minimally displaced fractures (i.e., Gartland type 2) also needs ORIF.7\n\nThe high incidence of SHF makes the decision of which surgical approach to perform crucial. Surgical approaches to manage elbow injuries can be performed with the anterior, lateral, medial, or posterior approach. There is no clear evidence of which approach is superior based on the functional, cosmetic, and radiological outcomes. Some of the surgical approaches that are commonly performed are the lateral and posterior approaches. Our study found that the lateral approach gave superior results to the posterior approach in the excellent subgroup assessment using Flynn's criteria for functional and cosmetic outcomes. It was also superior in the good subgroup for functional outcome. However, these differences were not statistically significant. A lateral approach is an approach with the least exposure to the elbow's essential structures than other approaches. It also has fewer surgical wounds that could interfere with elbow joint range of motion.20\n\nThis study also found that the lateral approach resulted in fewer poor outcomes than the posterior approach as evaluated using Flynn's criteria in the functional and cosmetic assessments. In other words, the lateral approach had an overall better result than the posterior approach, but this difference was not statistically significant. There is a considerable amount of damage to the triceps muscle in the posterior approach, which can interfere with the muscle's function postoperatively, causing as high as 6% muscle strength reduction compared to preoperative conditions.15\n\nThe lateral surgical approach is quite popular because it has the least risk of damaging vital structures such as the ulnar nerve, brachial artery, and capsule ligament at the elbow compared to other surgical approaches. From the cosmetic point of view, the lateral approach’s surgical wound is preferred because it is less visible than the other approaches. Moreover, the lateral approach is a safe approach due to the good visual field of the elbow anatomy and adequate exposure to the radiocapitellar compartment. This approach is easily carried out through the internervous plane, which minimizes nervous injury so that the risk of iatrogenic nerve damage is minimal. Besides, the lateral approach has a better fracture perspective than other approaches.20–23\n\nIn addition, the lateral approach is safer because less soft tissue is dissected, avoiding ulnar nerve damage. In cases requiring ORIF, the lateral approach is minimally invasive with minimal soft tissue dissection compared to the posterior approach. This is associated with the dissection or division of the triceps muscles, which often experiences more postoperative adhesions.23 However, soft tissue swelling is frequently found in the lateral approach, especially when combined with the medial approach to obtain better surgical exposure. Still, there is no consensus on which approach is superior.24 In addition, patients treated with a lateral approach tend to have fewer unstable fractures, complications, and re-operations. Previous research has shown that the lateral approach results are very satisfying, which shows that approximately 67-91.8% of them were successful.25 This finding is similar to the study conducted by Sarrafan et al., who reported that 90.9% of 33 patients who underwent the lateral approach obtained excellent results.23\n\nMeanwhile, on the other hand, the posterior surgical approach is popular because it has a shorter operating time compared to other approaches.19 However, this surgical approach is sometimes avoided by some surgeons because the triceps muscle is damaged in the process of reaching the fracture line.26 Nevertheless, a study conducted by Chen et al. reported the posterior approach’s superiority compared to anterior and medial approaches in terms of surgery duration and blood loss during elbow surgeries. They found that the shortest surgery duration was the posterior approach (62.9 ± 7.4 minutes), which was shorter than the anterior and medial approaches (64 ± 7.6 and 73.7 ± 7.3 minutes, respectively). Besides, the posterior approach resulted in less blood loss compared to the anterior and medial approaches (135.8 ± 44.7, 147.1 ± 42.7, and 171.3 ± 34.6 ml, respectively).27\n\nIn the present study, both lateral and posterior surgical approaches resulted in satisfactory results in more than 90% of the cases analyzed. Although the posterior approach has been associated with several complications such as decreased strength of triceps muscles, previous studies have shown that the functional and cosmetic results were comparable to medial and lateral approaches. Moreover, the posterior approach’s advantage such as a wider surgical field of view allows a trouble-free reduction process, resulting in shorter surgery time. Thus, the posterior surgical approach should always be considered whenever appropriate.28\n\nThe limitation of the current study is the language restriction to only English-language articles; thus, we may have missed other eligible studies written in other languages. Another limitation is the low number of studies that were included in the analysis. Moreover, all of the included studies were level III studies. Thus, the present review’s evidence level may not be the highest, as we did not find any randomized controlled trials (RCTs). However, we believe that our search strategy was comprehensive and robust. Moreover, we conducted a thorough bias analysis based on the Cochrane recommendation. Thus, our results represent the current best evidence on this topic. Future studies should conduct high-quality original research, preferably RCT, to provide better evidence. Moreover, a study comprising a direct comparison of all existing approaches for SHF management is still needed.\n\n\nConclusion\n\nBoth lateral and posterior surgical approaches resulted in satisfactory functional and cosmetic outcomes according to Flynn’s criteria. The two surgical approaches were comparable in terms of giving desirable functional and cosmetic outcomes for the management of SHF in children. However, the choice of surgical approach preference should be based on surgeons’ consideration in accordance with their experience and expertise.\n\n\nReporting guidelines\n\nFigshare: PRISMA checklist and flowchart for 'Lateral versus posterior surgical approach for the treatment of supracondylar humeral fractures in children: a systematic review and meta-analysis'. https://doi.org/10.6084/m9.figshare.14740545.v1.29\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: Appendix 1 search strategy. https://doi.org/10.6084/m9.figshare.14740584.v1.30\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nBadkoobehi H: Current concepts review: Management of the pulseless pediatric supracondylar humeral fracture. J Bone Jt Surg - Am Vol. 2014; 97(11): 937–43. PubMed Abstract | Publisher Full Text\n\nHolt JB: Understanding the Epidemiology of Pediatric Supracondylar Humeral Fractures in the United States: Identifying Opportunities for Intervention. J Pediatr Orthop. 2018; 38(5): e245–51. PubMed Abstract | Publisher Full Text\n\nZorrilla S, de Neira J, Prada-Cañizares A, et al.: Supracondylar humeral fractures in children: current concepts for management and prognosis. Int Orthop. 2015; 39(11): 2287–96. PubMed Abstract | Publisher Full Text\n\nSullivan JA, Gregory JR, Wiley KF, et al.: Supracondylar Humeral Fracture Documentation: A Performance Improvement Study. J Pediatr Orthop. 2019; 39(10): E777–81. PubMed Abstract | Publisher Full Text\n\nHoushian S, Mehdi B, Larsen MS: The epidemiology of elbow fracture in children: Analysis of 355 fractures, with special reference to supracondylar humerus fractures. J Orthop Sci. 2001; 6(4): 312–5.\n\nKazimoglu C, Çetin M, Şener M, et al.: Operative management of type III extension supracondylar fractures in children. Int Orthop. 2009; 33(4): 1089–94. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWingfield JJ, Ho CA, Abzug JM, et al.: Open Reduction Techniques for Supracondylar Humerus Fractures in Children.2015; 72–80. PubMed Abstract | Publisher Full Text\n\nKoudstaal MJ, De Ridder VA, De Lange S, et al.: Pediatric supracondylar humerus fractures: The anterior approach. J Orthop Trauma. 2002; 16(6): 409–12. PubMed Abstract | Publisher Full Text\n\nFlynn JC, Matthews JG, Benoit RL: Blind pinning of displaced supracondylar fractures of the humerus in children. Sixteen years’ experience with long-term follow-up. J Bone Joint Surg Am. 1974 Mar; 56(2): 263–72. PubMed Abstract\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 | Free Full Text\n\nSterne JAC, Savović J, Page MJ, et al.: RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366: 1–8. PubMed Abstract | Publisher Full Text\n\nSterne JA, Hernán MA, Reeves BC, et al.: ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355: 4–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeeks JJ, Higgins JPT, Altman DG; Group CSM: Analysing data and undertaking meta‐analyses. Cochrane Handb Syst Rev Interv. 2019; 241–84.\n\nGökçer U, Fatih Y, Mehmet E, et al.: Comparison of the lateral and posterior approaches in the treatment of pediatric supracondylar humeral fractures. J Pediatr Orthop Part B. 2018; 27(2): 108–114. PubMed Abstract | Publisher Full Text Reference Source\n\nKizilay, Aktekin, Ozsoy EA, et al.: Gartland Type 3 Supracondylar Humeral Fractures in Children: Which Open Reduction Approach Should Be Used after Failed Closed Reduction? J Orthop Trauma. 2017; 31(1): e18–23. PubMed Abstract | Publisher Full Text Reference Source\n\nTürkmen F, Toker S, Kesik K, et al.: Comparison of lateral versus triceps-splitting posterior approach in the surgical treatment of pediatric supracondylar humerus fractures. Ulus Travma Acil Cerrahi Derg. 2016 Sep; 22(5): 483–8. PubMed Abstract | Publisher Full Text Reference Source\n\nBamrungthin N: Comparison of posterior and lateral surgical approach in management of type III supracondylar fractures of the humerus among the children. J Med Assoc Thail. 2008 Apr; 91(4): 502–6. PubMed Abstract Reference Source\n\nBasaran SH, Ercin E, Bilgili MG, et al.: A new joystick technique for unsuccessful closed reduction of supracondylar humeral fractures: minimum trauma. Eur J Orthop Surg Traumatol. 2015 Feb; 25(2): 297–303. PubMed Abstract | Publisher Full Text Reference Source\n\nBamrungthin N: Comparison of posterior and lateral surgical approach in management of type III supracondylar fractures of the humerus among the children. J Med Assoc Thai. 2008 Apr; 91(4): 502–6. PubMed Abstract\n\nHussain S: Open reduction and internal fixation for displaced supracondylar fractures of the humerus in children with crossed K-wires via lateral approach. Chinese J Traumatol - English Ed. 2014; 17(3): 130–5. PubMed Abstract | Publisher Full Text\n\nSlobogean BL, Jackman H, Tennant S, et al.: Iatrogenic ulnar nerve injury after the surgical treatment of displaced supracondylar fractures of the humerus: number needed to harm, a systematic review. J Pediatr Orthop. 2010; 30(5): 430–6. PubMed Abstract | Publisher Full Text\n\nSibly TF, Briggs PJ, Gibson MJ: Supracondylar fractures of the humerus in childhood: range of movement following the posterior approach to open reduction. Injury. 1991; 22(6): 456–8. PubMed Abstract | Publisher Full Text\n\nSarrafan N, Nasab SAM, Ghalami T: Treatment of displaced supracondylar fracture of the humerus in children by open pining from lateral approach: An investigation of clinical and radiographical results. Pak J Med Sci. 2015; 31(4): 930–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeena M, Singh K, Meena S, et al.: Lateral Approach Versus Combined Lateral and Anteromedial Approach for Surgical Treatment of Terrible Triad of Elbow: A Meta-Analysis. Bull Emerg Trauma. 2020; 8(1): 4–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZamzam MM, Bakarman KA: Treatment of displaced supracondylar humeral fractures among children: Crossed versus lateral pinning. Injury. 2009; 40(6): 625–30. PubMed Abstract | Publisher Full Text\n\nAktekin CN, Toprak A, Ozturk AM, et al.: Open reduction via posterior triceps sparing approach in comparison with closed treatment of posteromedial displaced Gartland type III supracondylar humerus fractures. J Pediatr Orthop Part B. 2008; 17(4): 171–8. PubMed Abstract | Publisher Full Text\n\nChen HW, Teng XF: A comparative study on the validity and reliability of anterior, medial, and posterior approaches for internal fixation in the repair of fractures of the coronoid process of the ulna. Eur J Med Res. 2018; 23(1): 1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUzer G, Yildiz F, Elmadağ M, et al.: Comparison of the lateral and posterior approaches in the treatment of pediatric supracondylar humeral fractures. J Pediatr Orthop B. 2018 Mar [cited 2020 Oct 5]; 27(2): 108–14. PubMed Abstract | Publisher Full Text Reference Source\n\nIrianto KA, Pradana IPGP, De Vega B: PRISMA checklist and flowchart for 'Lateral versus posterior surgical approach for the treatment of supracondylar humeral fractures in children: a systematic review and meta-analysis'. figshare. Journal Contribution. 2021.Publisher Full Text\n\nIrianto KA, Pradana IPGP, De Vega B: Search strategy for 'Lateral versus posterior surgical approach for the treatment of supracondylar humeral fractures in children: a systematic review and meta-analysis'. figshare. Journal Contribution. 2021.Publisher Full Text"
}
|
[
{
"id": "89737",
"date": "19 Aug 2021",
"name": "Yudha Mathan Sakti",
"expertise": [
"Reviewer Expertise Orthopaedic and traumatology"
],
"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 the paper, the controversies regarding the topic of comparing approaches for supracondylar fractures in children is clinically relevant.\nThis study has an interesting background that evaluates the management of supracondylar humeral fracture (SHF) in children with the main concern of chosen approaches. Focus descriptions of comparing the lateral and posterior approaches for SHF with systematic review can be applied for decision making in the clinical setting; therefore, making this study a valuable contribution for managing SHF as the most common type of fracture in children.\nSpecific description regarding the study may improve the narrative and enlighten better of the objective.\nIntroduction:\nThe significant importance of good management for SHF is needed and well described in the introduction. The authors also describe the type of approaches and options to use and their limitation. Improvements are needed to describe the benefits and shortcomings in each approach to better explain the objective of this paper in comparing the lateral and posterior approaches.\n\nMethods:\nThe inclusion criteria used to select the studies to be enrolled in this paper is rigorous and well thought; however, the authors' reason to use Flynn’s criteria as a comparative measure between studies is needed.\n\nDescription of whether each of the chosen papers directly used the criteria or the authors’ method of conclusion to generate the papers’ findings to be put in Flynn’s classification is still needed.\n\nResults:\nRobust evaluation and selection are showed with the final 5 case-control studies included in this study. Description and bias evaluation is beneficial and creates a strong perspective to support the findings.\n\nFrom Table 4 (Patients’ outcome based on Flynn’s criteria), the authors conclude no significant difference on each functional and cosmetic findings between each paper in the qualitative analysis. This result is well depicted and described the objective of this study. Despite the findings, the authors’ method on how to conclude each paper in the qualitative evaluation is needed to provide a better description.\n\nClassifying each functional and cosmetic result from each paper and quantitatively compare them give a good insight into this literature review. These findings will give a beneficial perspective between the two approaches with methodical guidance led by this study.\n\nDiscussion and Conclusion:\nThe study answered the objective with good methodical reasoning. Significant knowledge and rationale of each approach is well described. Advantageous and limitations for each approach is thoroughly explained with correlation to this study’s finding. Overall, this study will give valuable inputs and contributions to clinicians based on the conducted literature review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? 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": "92398",
"date": "21 Sep 2021",
"name": "Prateek Behera",
"expertise": [
"Reviewer Expertise Pediatric Orthopaedics",
"Deformity Correction and Complex Trauma."
],
"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\nBased on the provided objectives of the study, the authors have attempted to find out the best approach for open reduction of the supracondylar humerus (SCHF) in children. While the authors have followed all the recommended steps for conducting a systematic review, the actual usefulness of this review for a practicing pediatric orthopedic surgeon dealing with SCHFs is a bit limited. The reasons for this observation are mentioned below:\nThe study looks at only two approaches for a common fracture - the lateral and posterior approaches - but has missed out on the anterior and medial ones. The indications for an open reduction include irreducible fractures and fractures with neuro-vascular involvement. Wingfield et al.1 have described the details of how an open reduction becomes necessary in many cases and how an approach can be chosen. In their review, they have mentioned the advantages and disadvantages of different approaches in detail. Reitman et al.2 studied their patients with SCHF and have mentioned that they prefer to approach through the ruptured periosteum so as not to injure the intact periosteum. If one follows this concept, then also the anterior approach might be the commonest one to be used. Thus, there is a selection bias in the study with the choice of approaches being only two. Ideally, the authors should have chosen studies on all the approaches and then performed the analysis. The result coming out of that comprehensive systematic review and meta-analysis would be the one that most pediatric Orthopaedic surgeons would like to see.\n\nThe stated objective of the study was to identify the best approach. Ideally, the best approach would be the one with the least difficulty in exposure, the best chances of providing a near anatomical reduction, the least number of complications, the best post-operative radiological outcome, and the best clinical and functional outcomes. Unfortunately, this study has tried to answer the research question using only one tool - the clinical and radiological outcome (using the system proposed by Flynn et al.). The authors should have included the complications, fixation failures, and other related issues in addition to the Flynn criteria.\nIn view of the two major points made above, in my opinion, the authors should be encouraged to expand the scope of the analysis and include all the approaches and focus on difficulties encountered, complications, reduction quality, loss of reduction, and clinical and functional outcomes. This would make the study more useful.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": [
{
"c_id": "7431",
"date": "18 Nov 2021",
"name": "komang irianto",
"role": "Author Response",
"response": "RESPONSE TO REVIEWERS Dear Dr. Prateek Behera, The authors would like to thank you for reviewing our submission. Questions: The study looks at only two approaches for a common fracture - the lateral and posterior approaches - but has missed out on the anterior and medial ones. The indications for an open reduction include irreducible fractures and fractures with neuro-vascular involvement. Wingfield et al. have described the details of how an open reduction becomes necessary in many cases and how an approach can be chosen. In their review, they have mentioned the advantages and disadvantages of different approaches in detail. Reitman et al. studied their patients with SCHF and have mentioned that they prefer to approach through the ruptured periosteum so as not to injure the intact periosteum. If one follows this concept, then also the anterior approach might be the commonest one to be used. Thus, there is a selection bias in the study with the choice of approaches being only two. Ideally, the authors should have chosen studies on all the approaches and then performed the analysis. The result coming out of that comprehensive systematic review and meta-analysis would be the one that most pediatric Orthopaedic surgeons would like to see. Answer: As stated in the manuscript, we compared the results of lateral and posterior approaches, given that the two approaches are the most common approaches performed by surgeons in a limited setting where C-arm is unavailable. The gold standard management of supracondylar fracture, which is closed reduction followed by percutaneous pinning, could not be performed. The open surgery is planned based on the clinical pathway of supracondylar fracture. Anterior approach is mandated when vascular lesion is suspected. We have added this information to the manuscript. Question: The stated objective of the study was to identify the best approach. Ideally, the best approach would be the one with the least difficulty in exposure, the best chances of providing a near anatomical reduction, the least number of complications, the best post-operative radiological outcome, and the best clinical and functional outcomes. Unfortunately, this study has tried to answer the research question using only one tool - the clinical and radiological outcome (using the system proposed by Flynn et al.). The authors should have included the complications, fixation failures, and other related issues in addition to the Flynn criteria. Answer: The main outcomes of supracondylar humeri management are function and cosmetic as established by Flynn et al., where surgeons and patients could objectively evaluate the outcomes. The follow up time in months was reported by all included studies. The fixation failure, skin tract infection, and other related complications had been treated promptly and were considered a part of the functional and cosmetic outcomes."
}
]
}
] | 1
|
https://f1000research.com/articles/10-573
|
https://f1000research.com/articles/10-1080/v1
|
25 Oct 21
|
{
"type": "Case Report",
"title": "Case Report: Stem cell therapy in amyotrophic lateral sclerosis",
"authors": [
"Ala'a A. Hassan",
"Jeananne Elkins",
"Hisham Y. Hassan",
"Jeananne Elkins",
"Hisham Y. Hassan"
],
"abstract": "Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to loss of upper and lower motor neurons at both spinal and bulbar levels.\n\nFor patients with ALS rehabilitation is important to maintain functional independence, ensure safety and optimize quality of life but is not curative. Stem cell therapy (SCT) provides a new approach to treat previously incurable diseases although peer reviewed published evidence has shown no benefit in ALS for slowing disease progression or functional loss.\n\nThis case report presents a patient with ALS who underwent SCT but deteriorated rapidly after the procedure. Whether the deterioration was due to the natural progress of the disease or expedited by SCT remains unknown. The ethical considerations of how marketing influences healthcare and individuals’ decisions in desperate situations along with reasons for taking desperate measures are discussed. Patient education and open communication with ALS patients are imperative in gaining patient satisfaction and overcoming ill effects that marketing could have on unconventional methods of intervention. Raising awareness about the availability and access to multidisciplinary care, the timing of decisions with regards to symptom management and end of life care have proven to enhance the quality of life for such patients.",
"keywords": [
"Amyotrophic lateral sclerosis",
"stem cell therapy",
"physical therapy",
"rehabilitation"
],
"content": "Introduction\n\nAmyotrophic lateral sclerosis (ALS), an incurable and fatal motor neuron disorder, leads to progressive destruction and loss of upper and lower motor neurons at both spinal and bulbar levels.1 Worldwide, two to five cases per 100,000 individuals per year are diagnosed with ALS.2-4 The average age of onset of ALS is between 50-65 years old, and it is more common in men.1 The cause of the familial type of ALS is mutations in several genes.1 The cause of sporadic cases which represent 90-95% of all cases is largely unknown, but most probably includes a combination of environmental and genetic factors.2 The symptoms occur in a gradual and sporadic pattern with progressive deterioration resulting in an average lifespan of 3-5 years after diagnosis.5 By the time the disease becomes noticeable, almost 80% of motor neurons have been lost.3 The most common symptoms are distal or proximal muscle weakness of upper and lower limbs, fasciculation and spasticity.1,3 Once bulbar levels are affected then dysphagia and dysarthria become apparent leading to weight loss and anorexia.1,3 At advanced stages of the disease, the respiratory system is affected leading to respiratory failure with the need for assisted ventilation to sustain life.1,3\n\nThe only Federal Drug Administration (United States) approved drug for ALS, Riluzole, reduces the disease progression and improves the survival by only 3-6 months.3,5 Therefore, ALS is managed predominantly through supportive care and comprehensive multidisciplinary management.5,6 Considering the progressive nature of the disease, patients are tempted to seek any available intervention to modify or cease the progression of the disease. Despite the controversy associated with its efficacy and ongoing research, stem cell therapy is one of the few available interventions attempted for ALS.7\n\n\nCase presentation\n\nA 52-year-old Arab male working as a military officer and married with three children presented to the neurology outpatient clinic in October 2016. His past medical history revealed appendectomy (2012) and colon cancer (2013). Family history was clear and not known for any genetic diseases. His initial symptoms were weakening of the right upper limb associated and painful spasms. He did not have other symptoms in the neural axis and was functionally independent. He scored 126 points on the Functional Independence Measure (FIM)8 and 24 points on the Dynamic Gait Index (DGI)9 indicating he was functionally independent and had excellent balance with no risk of falls. However, electrophysiological testing confirmed ALS. At the early stage of ALS his right upper limb showed significant atrophy in comparison to the left side with clear spontaneous fasciculation involving the deltoid and pectoralis muscles. His reflexes were exaggerated with positive Hoffman signs but examination of other limbs was unremarkable. The patient was referred to physical therapy in October 2016 to maintain his functional level and activity. Physical rehabilitation focused on general strengthening exercises at moderate intensity, balance and plyometric training and aerobic training. He received therapy 3 times a week for 8 weeks before experiencing further functional decline.\n\nIn the following 6-8 months, the ALS progressed and the patient’s function declined. He lost his ability to grip objects and developed a shuffling gait pattern but was still independent. He was independent in transfers; however, he was falling more often. The FIM score declined to 96 points indicating he required minimal to moderate assistance with activities of daily living.8 His DGI declined to 10 points categorizing him at high risk of falls.9\n\nAt this point in time, the patient began considering undergoing stem cell therapy (SCT) because of his declining function. Educational information about how SCT is still in the research phase and that no conclusive evidence for effectiveness in ALS has been established was provided to the patient. However, the patient had confirmed his decision to undergo SCT in Ukraine. Per the patient reports, he received SCT on two consecutive days. The first day consisted of an intravenous drip-fed administration of 2.1 ml of embryonic stem cells. The second day subcutaneous implantation of the 5.1 ml of embryonic stem cells in the frontal abdominal wall was administered. Of note, the SCT were negative from all bacterial, viral and intracellular infections.\n\nComparing this sample to the established human clinical trials published in Goutman et al,10 no trial used embryonic stem cells and the intraspinal route of administration was more common than the intravenous route. No mention of immunosuppression medications was indicated in the patient report. Although the consensus regarding the dosage of stem cells is variable and inconclusive, the amount of stem cells administered in the studies ranged between 300-600 micrograms/day over 5-6 days; thus, this patient’s dosage does not match that found in the literature.11 Moreover, the patient did not receive a follow-up session after undergoing the procedure.\n\nSix months post SCT, he had lost functional ability and was primarily wheelchair bound. He was still able to walk with a gutter frame with assistance for a distance of 10-20 meters before becoming fatigued. He was dependent on his family for his basic activities of daily living and was at high risk of falls (FIM Score 86 points8 and DGI 4 points9). Physical therapy focused on maintaining the available function and strength at this stage through functional training of lower limbs including sit-to-stand exercises, practicing transfers and gait training. Upper limb and balance training were eliminated as the patient lost complete muscle power and ability. The treatment changed session by session based on the patient’s physical ability and psychological wellbeing. The patient died in March 2021 at the age of 57 years - 5 years from the date of the diagnosis in 2016.\n\n\nDiscussion\n\nThe question of whether SCT expedited this deterioration or whether this functional decline is part of the natural disease course remains unanswered. There is a lack of confirmatory evidence that exercise training during physical therapy sessions causes deterioration in patient condition. Exercises focusing on strength, endurance and aerobic training at moderate intensity are not associated with delaying or expediting the disease process. However, over-exertion should be avoided as it can induce muscle damage in addition to fatigue and pain.5,12\n\nThe main characteristics of stem cells are self-renewal, proliferation and full differentiation into the needed cell type.13 Therefore, SCT provides a new horizon to attempt to treat the incurable diseases although no confirmative evidence has been established yet. The aims of SCT in neurological conditions are to replace the lost or damaged nerve cells, restore the homeostasis of the central nervous system, protect the unaffected surrounding tissues, and enhance the endogenous repair processes initiated by the body.13 Trials of SCT for ALS, Parkinson’s disease, stroke, spinal cord injury and epilepsy have been primarily carried out in animals,11 but extrapolating results to human trials is still challenging.\n\nThe major challenge with SCT in ALS is that the pathophysiological mechanisms of ALS are varied including mitochondrial impairment, oxidative stress, neuronal cytotoxicity, altered gene expression and cell death.3 Consequently, to decipher the exact mechanisms responsible for disease onset and progression is mysterious, and to implement a treatment plan aiming to target these multiple mechanisms becomes even more challenging.10,13 Goutman et al10 contend with SCT there are no clear pharmacokinetic and pharmacodynamics markers thus making it difficult to decipher its effectiveness or adverse reactions. This also poses the challenge of ensuring the graft’s survival, and the outcome measures used in ALS patients, such as ALS Functional Rating Scale-Revised,14 reflect on the functional status of a patient, but not on the motor neuron environment. Hence, the efficacy of SCT and new motor neuron formation remains unknown. The outcome measures used in ALS research must be sensitive to capture changes in the course of the disease.4\n\nALS disease, like many other neurological diseases, has variable rates of progression among patients. The type of ALS, bulbar or spinal, has an effect on the prognosis. Questions regarding the dosage of SCT and type of the most effective stem cell in this patient population remain unknown and require further research. Would it be beneficial to administer SCT in the early or late stages of ALS? Is there a criterion for patient selection for ALS? More research is required to identify the effective protocol for SCT in this patient population.\n\nThis patient is truly an example of how desperate people take desperate measures and make desperate choices even though those measures could potentially worsen their quality of life. Being a burden on the family is a major concern for patients and a reason for these desperate decisions. Additionally, neither patients nor their families may be ready for the “final stage” i.e. facing death. Uncertainty of timing may be another reason and accepting the medical condition may be troublesome for some patients and their family members.10 Moreover, undergoing surgeries or novel procedures including SCT could provide patients and their families with reassurance that they have exhausted all the interventional options regardless of the outcome.12\n\n\nEthical and clinical recommendations\n\nPatient education and communication reduces anxiety and fear among patients. The way the diagnosis is communicated at the first step determines the doctor-patient relationship. Spending adequate time discussing the diagnosis is a predictor of higher patient satisfaction with medical care.12 Discussing the diagnosis in the presence of family members and arranging regular meetings after the first session to address further concerns reduces patient anxiety.12 Lack of or inappropriate communication from the physicians and healthcare workers can lead to patients searching for and locating alternative methods of intervention.12 In addition, many patients are unaware of evidence-based medicine and may be attracted to marketing campaigns.\n\nSpecifically for patients with ALS there are three critical points in healthcare. These are the timing and delivery of the diagnosis, the availability and access to multidisciplinary care, and the timing of decisions with regards to symptom management and end of life care.15 This standard of care has resulted in improved quality of life for patients, increased survival and reduced hospital admission or length of stays.15 Hogden et al 15 suggest palliative care for patients with ALS is appropriate from the time of diagnosis and the involvement of the palliative care specialist should fluctuate based on the patient and family’s needs as the disease progresses.\n\nTechnological advancements in healthcare have worked immensely to prolong terminally ill patients’ lives through methods including mechanical ventilation, tracheostomy, and feeding tubes. However, while these advancements can prolong lives, they do not enhance the quality of life in fragile patients.12 Focusing on mental well-being, providing comfort, minimizing pain, enjoying quality time with family and focusing at the participation level of function are essential to improve quality of life.12 Group therapy could also provide social support and promote added benefits.16\n\nThe impact of marketing on healthcare decisions as well as how companies may take advantage of terminally sick patients and their families is often underestimated. Many companies extoll the benefits of SCT whether for the sake of gaining profit or having participants to give their consent for human clinical trials. Patients may believe if they agree to undergo a clinical trial, they will be receiving the best medical care available or care that is not available to them with their local physician or specialist.10 Marketers advocate that patients are consumers of healthcare services and it is their absolute right to select whatever treatment they want even if the knowledge available regarding the intervention is not conclusive.10 Under this approach, marketers sell their products by purporting to respect the patient’s interest and offer the patient as being the expert to weigh the risks against the benefits.\n\nAlthough technological advancements and interventions such as SCT provide hope for complex neurological conditions, controversial scientific evidence disproving their efficacy could impede recommending them to patients. The strength of this paper is in highlighting the ethical considerations that are associated with clinical decision-making in such complicated patient conditions. Proficient clinical skills, open and transparent communication and patient education are imperative in such clinical cases despite the attempts made by marketers of healthcare companies to gain profit. The major limitation of this paper is it being a case report thereby limiting its extrapolation to other patient populations. Complex and progressive neurological conditions such as ALS have individual differences from one case to another, which makes each case management distinctive and tailored to the patient’s needs.\n\n\nConclusion\n\nProgressive neurological conditions including ALS are challenging from a clinician’s perspective in terms of medical management and often overwhelming from a patient and family perspective. Coping and accepting the functional deterioration as well as the inevitable death associated with ALS is difficult. Acknowledging the scientific advancements including SCT can provide hope; however, the lack of scientific evidence to prove its effectiveness in ALS imposes challenges in terms of finding a cure. Marketers advocate on these advancements tempting desperate patients to make decisions despite the inconclusive evidence. Communication and collaboration of multidisciplinary team management with the patient and family members in these situations is crucial to overcome the negative impact that marketing would have on their decision-making.\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 the participant’s details was obtained from the participant’s spouse.",
"appendix": "References\n\nZarei S, Carr K, Reiley L, et al.: A comprehensive review of amyotrophic lateral sclerosis. Surg. Neurol. Int. 2015; 6: 171–197. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMEDLINE PLUS: Amyotrophic Lateral Sclerosis.August 18, 2020.\n\nOrsini M, Oliveira AB, Nascimento OJM, et al.: Amyotrophic Lateral Sclerosis: New Perpectives and Update. Neurol. Int. 2015; 7(5885): 39–47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen KS, Sakowski SA, Feldman EL: Intraspinal Stem Cell Transplantation for Amyotrophic Lateral Sclerosis. Ann. Neurol. 2016; 79(3): 342–353. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMajmudar S, Wu J, Paganoni S: Rehabilitation in Amyotrophic Lateral Sclerosis: Why it matters. Muscle Nerve. 2014; 50(1): 4–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPaganoni S, Karam C, Joyce N, et al.: Comprehensive Rehabilitative Care Across the Spectrum of Amyotrophic Lateral Sclerosis. NeuroRehabilitation. 2015; 37(1): 53–68. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBiehl JK, Russell B: Introduction to Stem Cell Therapy. J. Cardiovasc. Nurs. 2009; 24(2): 98–103. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPike S, Cusick A, Wales K, et al.: Psychometric properties of measures of upper limb activity performance in adults with and without spasticity undergoing neurorehabilitation–A systematic review.2021; 16(2): e0246288.\n\nMoore J, Potter K, Blankshain K, et al.: A Core Set of Outcome Measures for Adults With Neurologic Conditions Undergoing Rehabilitation a Clinical Practice Guideline.2018; 42(3): 174–220.\n\nGoutman SA, Chen KS, Feldman EL: Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis. Neurotherapeutics. 2015; 12(2): 428–448. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdami R, Scesa G, Bottai D: Stem cell transplantation in neurological diseases: improving effectiveness in animal models. Front. Cell Dev. Biol. 2014; 2(17): 1–28. Publisher Full Text\n\nKim C, Lee HC, Sung J-J: Amyotrophic Lateral Sclerosis - Cell Based Therapy and Novel Therapeutic Development. Exp Neurobiol. 2014; 23(3): 207–214. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLunn JS, Sakowski SA, Feldman EL: Stem cell therapies for amyotrophic lateral sclerosis: Recent advances and prospects for the future. Stem Cells. 2014; 32(5): 1099–1109. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChew S, Burke KM, Collins E, et al.: Patient reported outcomes in ALS: characteristics of the self-entry ALS Functional Rating Scale-revised and the Activities-specific Balance Confidence Scale. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. March 26, 2021; 1–11. PubMed Abstract | Publisher Full Text\n\nHogden A, Foley G, Henderson RD, et al.: Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J. Multidiscip. Healthc. 2017; 10: 205–215. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLoutfy M: Changing the Rules in Times of Crisis: Do Desperate Times Allow Desperate Measures?. AMA J. Ethics. 2006; 8(4): 214–218. Publisher Full Text"
}
|
[
{
"id": "97829",
"date": "01 Nov 2021",
"name": "Dr. Julie Sprakel",
"expertise": [
"Reviewer Expertise Breast Cancer",
"Guideline Development"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIt is a constructive and comprehensive piece of work. The authors take a unique look from a different standpoint when they address \"ethical and clinical recommendations\".\nThe impact of marketing \"new scientific treatments\" with no confirmative evidence could be further discussed in many other research articles and begs the question of \"governance\".\nThe authors clearly looked at a holistic picture of what can influence a patient and what lengths they are willing to go, for their health. It opens up to a further publication specifically around treatments without addressing harms and benefits.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "7381",
"date": "02 Nov 2021",
"name": "Alaa Hassan",
"role": "Author Response",
"response": "Thank you for your time to read and review this article. Thank you for your comments. I am glad that the take home message of how marketing could affect a patient's decision in pursuing treatments that lack scientific evidence is clearly portrayed to you and you agree with."
}
]
},
{
"id": "101768",
"date": "04 Jan 2022",
"name": "Ebrahim Rajab",
"expertise": [
"Reviewer Expertise Learning and Memory"
],
"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 focuses on the need for amyotrophic lateral sclerosis (ALS) patients to receive evidence-based advice, education, and multidisciplinary care in a collaborative and timely fashion. The authors highlight how the marketing of stem cell therapy (SCT) by private clinics/companies can influence patient decisions even though this treatment is currently experimental and of variable success.\nDetailed points\n\nAbstract\nMention the age and gender of the patient.\n\nAdd a sentence explaining that the patient elected to go overseas for SCT of their own accord.\n\nMention that the patient received physical therapy treatment.\n\nGive a brief time course for deterioration of symptoms.\n\nIntroduction section\nThe second paragraph, the final sentence should include more up-to-date references on SCT e.g. Mazzini et al. 20181; e.g. Morata-Tarifa et al., 20212) This section should end by stating the aim/purpose of this case report more clearly.\n\nCase Presentation section\nPlease add a reference in the 3rd paragraph, the sentence beginning “Educational information about how SCT is still in the research phase…”.\n\nDid the patient and/or his family provide their own viewpoint on the SCT treatment following return from overseas? Did their viewpoint change as the ALS deteriorated?\n\nThe authors could summarize the clinical course, FIM, and DGI results and observations in a table or figure. Also, the authors could add the stage of ALS if they feel it is appropriate.\nDiscussion section\nThe first paragraph should summarise the key points of the case report and link back to the aims of the case report.\n\nThe 2nd, 3rd and fourth paragraphs could be condensed given that their content is not the case report's primary focus. Please provide a sentence or two specifically on the benefits/issues of embryonic SCT given that this was the treatment in the present case.\nEthical and clinical recommendations\nSince the SCT was administered overseas, what additional ethical or clinical issues did this raise for the care team, if at all?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "7670",
"date": "10 Jan 2022",
"name": "Alaa Hassan",
"role": "Author Response",
"response": "Thank you very much Dr. Paul for your revision and insightful recommendations and edits. I agree with most of the points you have mentioned and I have accordingly made the necessary edits. Thank you for bringing new references to my attention and I have also added these to my paper. However, the only two points I did not address were having the results in tables, I did not address that because the numbers for the outcome measures were done on two or three sessions, and having them within the text with a brief interpretation of what they mean would suffice. There were no other outcome measures used with this patient to have a table of results displayed. The other point concerning having the procedure done overseas and whether that has any ethical issues or considerations I feel that I did not have enough information about the procedure. The patient was not given enough details and reports throughout the course of the procedure and it was difficult to access information especially since he was not given any follow-up appointments. As discussed in the paper, the family supported the patient in the decision not knowing what SCT really entails and how much research is out there to support its effectiveness. They mainly supported him because this intervention was simply not available in his home country. So, not having enough information about what has happened makes it difficult for me to discuss or make any points regarding that other than focusing on the aim of this paper which was how marketing for certain interventions might actually be deceiving. I thank you again for your time and valuable input which I have taken on board in making this paper worth indexing."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1080
|
https://f1000research.com/articles/10-1262/v1
|
08 Dec 21
|
{
"type": "Systematic Review",
"title": "Effects of exercise-based prehabilitation in children undergoing elective surgeries: a systematic review",
"authors": [
"Jean Noronha",
"Stephen Samuel",
"Vijay Pratap Singh",
"H Shivananda Prabhu",
"Jean Noronha",
"Vijay Pratap Singh",
"H Shivananda Prabhu"
],
"abstract": "Background: Prehabilitation is a therapeutic strategy involving preoperative physical exercises, nutritional support, and stress and anxiety reduction. This approach has been gaining popularity and has been seeing effective results in adults in terms of improving pre and postoperative outcomes. The purpose of this review was to summarise the evidence about the effects of exercise-based prehabilitation programs on various outcome measures in children post elective surgeries. Methods: PubMed, Scopus, Web of Science, PEDro, CINAHL/EBSCO and EMBASE electronic databases were searched from inception to June 2021. Based on the inclusion criteria, titles and abstracts were independently screened by the authors. After that, a data extraction table of the selected studies which included the participants, type, and details of exercise intervention, outcome measures and results were analysed after which the quality assessment of the studies was done. Results: The search yielded 2219 articles of which three articles fulfilled the inclusion criteria with two studies being randomized controlled trials and one being a quasi-experimental pre-post type of study. One randomized controlled trial was on the effects of exercise-based prehabilitation in reducing pulmonary complications post cardiac surgeries in children and the other two studies were on the effects of prehabilitation on functional capacity & pulmonary function. All the three articles found that exercise-based prehabilitation had a positive effect on children’s post-surgery. Conclusion: Although there is a paucity of evidence-based literature, we conclude based on the existing literature retrieved by our review that exercise-based prehabilitation improves postoperative outcomes and helps in reducing postoperative complications in children undergoing various surgeries.",
"keywords": [
"Pre-operative exercises",
"preoperative exercise",
"prehabilitation",
"exercise therapy",
"surgery",
"paediatric",
"children",
"adolescents"
],
"content": "Abbreviations used\n\nACBT: Active Cycle of Breathing Technique\n\nCG: Control Group\n\nFEV1: Forced Expiratory Volume 1\n\nFEV1/FVC Ratio: Tiffeneau-Pinelli index\n\nFVC: Forced Vital Capacity\n\nIG: Interventional group\n\nPEFR: Peak expiratory flow rate\n\nPOP: Postoperative Physiotherapy\n\nPOPE: Preoperative Physiotherapy Education\n\nPRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\n\nRCT: Randomized control trial\n\nROM: Range of Motion\n\nTUGT: Time up and Go test\n\n6MWT: Six-minute walk test\n\n9SCT: 9 Step climbing test\n\n10MWT: 10 minute walk test\n\n\nIntroduction\n\nMajor surgeries in children along with the deleterious effects of the condition that predisposes a child for the surgery lead to complications that need to be therapeutically managed in children.\n\nPrehabilitation is a multimodal type of approach that helps a patient planned for any major surgery and also allows them to prepare to, manage the stressors in the pre-surgical period and also undertake the necessary rehabilitation successfully so that they can return to their pre-operative state with better and improved outcomes.1,2 Prehabilitation encompasses pre-operative physical exercises, nutritional support, and stress and anxiety reduction.3,4 The concept of prehabilitation dates as far back as World War II and was initially started not as a part of the pre-surgical procedure.1 Prehabilitation has its first mentions in articles in 1942 where it raised the fact that military recruits would be medically screened and treated in respect to their health and comorbidities, resulting in a higher number of acceptances.1,5 and came to light post-2011 after the systematic review published by Valkenet et al. about prehabilitation before joint, cardiac and abdominal surgeries3,6\n\nPrehabilitation/preoperative exercise is a set of interventions done before surgery that helps the patient to be prepared for post-surgical stressors and also help improve their functional capacity (FC) through the exercises.1,7 Patients’ ability to function to their fullest capacity can deteriorate because of inactivity during the surgical period and even if the surgery has been successful there can be chances of deconditioning.1,8,9 Current studies and reviews done in prehabilitation concerning the adult population does show that there is improvement in the post-operative complications and length of stay and also in their post-operative pain.3,10 Therefore the concept of prehabilitation is said to not only help the patient prepare themselves before a major surgery for post-surgical complications, but it also helps the patient to understand the importance of it to reduce the complications, helping them promote physical fitness and also optimize their psychological wellbeing. This also helps the patients return to their normal levels of functionality that was present before surgery.11–13\n\nThis review aims at examining the current body of evidence in the area of exercise-based prehabilitation in children undergoing various elective surgeries.\n\n\nMethods\n\nA data search was made on PubMed, Scopus, Web of Science, PEDro, EMBASE, CINAHL/EBSCO from inception to June 2021. The terms used for search for the paediatric population were the following: infant [Mesh], child [Mesh], adolescent [Mesh], children. The terms preoperative exercise [Mesh], exercise [Mesh], exercise therapy [Mesh], breathing exercises [Mesh], preoperative exercises [Mesh] were used related to the intervention and for the population type: general surgery [Mesh], paediatrics/surgery [Mesh] and surgical procedures operative [Mesh] were the terms used. The search terms were combined with a Boolean operator ‘AND’ or ‘OR’ wherever applicable. The references of the included articles were also screened for possible relevant studies.\n\nThe articles were screened based on the following pre-set criteria. The inclusion criteria include 1) Studies that included participants in the age group of 0-18 years; 2) Studies that include children undergoing elective surgeries; 3) Studies published in English language and 4) were either randomized control trial (RCT), Non-RCT, single group post, case study and case series and the exclusion criteria included were 1) studies with participants undergoing a prehabilitation program other than exercise 2) studies that included participants above 18 years.\n\n\nResults\n\nAll the data retrieved from the databases, summing up to 2219 articles, were fed in the Mendeley Desktop v1.19.8 after which duplicates were removed. The articles were then screened through the titles and 181 articles were found eligible, following this the abstract screening removed 150 articles, after which full-text screening was done, and 29 papers were excluded, eventually yielding three papers that meet the inclusion criteria of this review. The PRISMA flow chart in Figure 1. Outlines details regarding the identification, screening, eligibility, and inclusion of the studies in this review.\n\nThe risk of bias scoring was done using the NIH Quality assessment scales as shown in Figure 2.14 The quality assessment scales were used depending on the type of study. Two separate scales were used for the pre-post study design and the RCT. The scales covered everything regarding the type, duration of the study, the sample sizes, characteristics of the population and about its randomization, the interventions used, and whether participants and therapists were blinded. A score of 9/12 was rated for the pre-post type of study done by Sharma N et al.15\n\nA score of 7/14 was given for the RCT done by Sharma N et al.16 and Felcar et al.17respectively.\n\nOf the three studies, the two studies included children scheduled for abdominal surgeries in the age group 5-17 years of age15,16 and the other study had children one-day-old to six-year-old with congenital heart disease who underwent heart surgeries.17\n\nAll of the three studies included exercise-based prehabilitation as the main form of intervention. Of the three studies, one study focused on the use of exercise-based prehabilitation in reducing pulmonary complications through chest physiotherapy, clearance techniques, support and guidance to parents, and early mobilization.17 The other two studies included the N-PARP protocol15 used for prehabilitation This protocol included exercises to be given from the pre-operative period till POD5 and included breathing exercises, ROM exercises, and ambulation.15,16\n\nFelcar et al.17 included the presence or absence of pulmonary complications as its major outcome measure. while Sharma N et al.15,16 had a pulmonary function and functional capacity (FC) as their main outcomes which included spirometer values and Six-minute walk test (6MWT) respectively and others being 10 minute walk test (10MWT), Timed up and go test (TUGT), chest expansion. A detailed explanation of the studies is given in Table 1.\n\nAbbreviations: RCT - Randomized control trial; IG - Interventional group; CG - Control Group; POPE - Preoperative Physiotherapy Education; POP - Postoperative Physiotherapy; ACBT - Active Cycle of Breathing Technique; ROM-Range of Motion; FVC-Forced Vital Capacity; FEV1 - Forced Expiratory Volume 1; FEV1/FVC Ratio - Tiffeneau-Pinelli index; PEFR - Peak expiratory flow rate; 6MWT - Six-minute walk test; 10MWT - 10 minute walk test; TUGT - Time up and Go test; 9SCT - 9 step climbing test.\n\nA data extraction table was made to summarize and cover all the details regarding the participants, study design, sample size, study groups, type and dosage of exercise intervention, outcomes measures, and conclusion for all the selected studies. A detailed description of the Data extraction is presented in Table 1.\n\n\nDiscussion\n\nThis systematic review aimed at identifying studies that gave an exercise-based prehabilitation intervention to children undergoing various surgeries. While searching articles for this review various studies were found that included post-operative exercise after surgery in children, but very few studies included prehabilitation in the routine clinical care of these patients.\n\nSharma N et al. published two studies in 202015 and in 202116 about the effects of prehabilitation on pulmonary function and FC in the patients undergoing elective abdominal surgeries and Felcar et al. studied its effects in the reduction of post-op pulmonary complications in children undergoing cardiac surgery.17\n\nIn the two studies conducted by Sharma N et al.15,16 the effects of prehabilitation on FC and pulmonary functions were studied using a spirometer as a measurement tool. There was a trend seen in both the studies that no major changes in the values of the spirometer (that includes Forced Vital Capacity (FVC), Forced Expiratory Volume 1 (FEV1), Tiffeneau-Pinelli index (FEV1/FVC ratio), Peak Expiratory Flow Rate (PEFR)) were seen in the pre-surgical period and on POD 5, but there was a decline seen from the pre-operative period to POD 1 and from POD1 to POD5. The only difference seen in the RCT16 compared to the pre-post study15 conducted by Sharma N et al. was that FVC improved post prehabilitation and surgery. Values of chest expansion seemed to be better in the IG than CG in the RCT.16 Lastly, one of the common findings in both the studies was that the values of 10MWT, TUGT, 9SCT were seen better in the CG of both studies rather than in the IG.15,16 This study implies that exercise-based prehabilitation when given in a proper format and incorporated well in routine care can have beneficial effects in children during the post-operative period.\n\nIn the study done by Felcar et al.,17 it was seen that children in the CG were seen to have a higher frequency of developing pulmonary complications such as pneumonia or atelectasis or both as compared to the IG that received both the treatment options, i.e., prehabilitation and post-operative exercises.17 This implies that children who received exercise-based prehabilitation have a lesser frequency of developing any other complications as compared to the children that didn’t receive prehabilitation.\n\nQuality assessment of each of the studies was done by using the NIH Quality assessment scale. Two different scales were used for each type of the study i.e. the pre-post type of study and the other for an RCT14 The Pre-post study was done by Neha et al.15 had a scoring of 9/12 which acc to their scale was categorized as fair. This study included clearly stated objectives, had a pre-set inclusion and exclusion criteria. The sample size was around 12 participants but enough to conclude about the effects of the N-PARP (prehabilitation protocol) in that set population and to conclude that the study could be done in a larger population. there is also no information regarding the blinding of the populations in this study.\n\nThe NIH Quality assessment is done for The articles of Felcar et al.,17 and Neha et al.16 scored them (7/14) and (7/14) respectively which according to their scale belonged to the fair category. Both these RCTs did not have any details regarding the blinding and concealment of the participants.\n\n\nConclusion\n\nAlthough few in number, the available literature leads us to the conclusion that exercise-based prehabilitation plays an important role in improving health-related outcome measures in children undergoing various surgeries.\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\nOpen Science Framework: PRISMA Checklist final.docx, https://doi.org/10.17605/OSF.IO/B3CPX.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nWright S, Wiechula R, McLiesh P: The effectiveness of prehabilitation for adults having elective surgery: a systematic review protocol. JBI database Syst. Rev. Implement Reports. 2016; 14(2): 78–92. PubMed Abstract | Publisher Full Text\n\nPatel BK, Hall JB: Perioperative physiotherapy. Curr. Opin. Anaesthesiol. 2013; 26(2): 152–156. PubMed Abstract | Publisher Full Text\n\nBanugo P, Fcai M, Amoako D, et al.: Prehabilitation.2017; 17(August): 401–5.\n\nDitmyer MM, Topp R, Pifer M: Prehabilitation in preparation for orthopaedic surgery. Orthop. Nurs. 2002; 21(5): 43–54. quiz 52. PubMed Abstract | Publisher Full Text\n\nPREHABILITATION, rehabilitation, and revocation in the Army. Br. Med. J. 1946; 1: 192–197. PubMed Abstract\n\nValkenet K, Van De Port IGL, Dronkers JJ, et al.: The effects of preoperative exercise therapy on postoperative outcome: A systematic review. Clin. Rehabil. 2011; 25(2): 99–111. Publisher Full Text\n\nKim DJ, Mayo NE, Carli F, et al.: Responsive measures to prehabilitation in patients undergoing bowel resection surgery. Tohoku J. Exp. Med. 2009; 217(2): 109–115. PubMed Abstract | Publisher Full Text\n\nPieper MLB: Perceptions of the waiting period before coronary artery bypass grafting.PubMed Abstract\n\nKillewich LA: Strategies to minimize postoperative deconditioning in elderly surgical patients. J. Am. Coll. Surg. 2006; 203(5): 735–745. PubMed Abstract | Publisher Full Text\n\nMina DS, Clarke H, Ritvo P, et al.: Effect of total-body prehabilitation on postoperative outcomes: a systematic review and meta-analysis. Physiotherapy. 2014; 100(3): 196–207. PubMed Abstract | Publisher Full Text\n\nCabilan CJ, Hines S, Munday J: The effectiveness of prehabilitation or preoperative exercise for surgical patients: a systematic review. JBI database Syst. Rev. Implement Reports. 2015; 13(1): 146–187. Publisher Full Text\n\nTopp R, Ditmyer M, King K, et al.: The effect of bed rest and potential of prehabilitation on patients in the intensive care unit. AACN Clin. Issues. 2002; 13(2): 263–276. PubMed Abstract | Publisher Full Text\n\nCarli F, Zavorsky GS: Optimizing functional exercise capacity in the elderly surgical population. Curr. Opin. Clin. Nutr. Metab. Care. 2005; 8(1): 23–32. PubMed Abstract | Publisher Full Text\n\nStudy Quality Assessment Tools|NHLBI, NIH: Reference Source\n\nSharma N, Sree BS, Aranha VP, et al.: Preserving pulmonary function and functional capacity in children undergoing open abdominal surgery: A one group pretest–posttest, quasiexperimental pilot trial. J. Pediatr. Surg. 2020; 55(10): 2191–2196. PubMed Abstract | Publisher Full Text\n\nSharma N, Sree BS, Samuel AJ, et al.: A randomized clinical trial in improving pulmonary function and functional capacity in pediatric open abdominal surgery. J. Pediatr. Surg. 2021 Mar 1 [cited 2021 Apr 23]; 56(3): 559–564. Publisher Full Text PubMed Abstract | Reference Source\n\nFelcar JM, Guitti JC d S, Marson AC, et al.: Preoperative physiotherapy in prevention of pulmonary complications in pediatric cardiac surgery. Rev. Bras. Cir. Cardiovasc. 2008; 23(3): 383–388. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "102366",
"date": "05 Jan 2022",
"name": "Forhad Akhtar Zaman",
"expertise": [
"Reviewer Expertise Communicable disease especially TB",
"HIV",
"Covid"
],
"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 think this is an excellent systematic review aimed at reviewing studies of exercise-based prehabilitation intervention to children undergoing various surgeries.\nThe strength of the study was that the review was done very meticulously and it followed all the required steps of systematic review. This will be an important addition to the existing literature. As the selection criteria was very robust & specific, only three out of a whole lot of studies could be selected for the review. Although few in number, I really like the way in which the discussion was done and evidence presented. I hope the authors will correct the few numerical errors which which has been mentioned in the report.\nI have only a couple of minor points of clarification:\nIn the Methodology section, it was not mentioned why only randomized controlled trials & quasi-experimental studies were selected.\n\nThere is a mismatch between the number of total eligible titles (181) & total removed (150), thus full-text articles assessed for eligibility should have been 31, but it is mentioned as 33 in the PRISMA Flow chart (Fig-1). Also, out of 33 full-text articles which was assessed for eligibility, 29 papers were excluded, leaving 4 papers that ultimately met the inclusion criteria, but it is mentioned as 3.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "7671",
"date": "04 Feb 2022",
"name": "Stephen Samuel",
"role": "Author Response",
"response": "Dear F1000Research Team, We thank the reviewer and the editorial team for taking out the time to conduct an in-depth review of our article. We thank you for the appreciation you have given us regarding this systematic review. We also thank you for the clarifications. The necessary changes have been made and addressed accordingly. The modified manuscript and the latest PRISMA flow chart with changes tracked in the word document have been uploaded. Reviewer Comment 1 \"In the Methodology section, it was not mentioned why only randomized controlled trials & quasi-experimental studies were selected.\" Reply – The following types of study designs, i.e., RCT (Randomized Controlled Trials), Non-RCT, Single group Pre-post, Case study, and series were to be included; but during the data extraction and reviewing process only RCT and quasi-experimental studies were retrieved Reviewer Comment 2 \"There is a mismatch between the number of total eligible titles (181) & total removed (150), thus full-text articles assessed for eligibility should have been 31, but it is mentioned as 33 in the PRISMA Flow chart (Fig-1). Also, out of 33 full-text articles which was assessed for eligibility, 29 papers were excluded, leaving 4 papers that ultimately met the inclusion criteria, but it is mentioned as 3.\" Reply- We thank the reviewer for the correction and we have made the necessary changes as suggested."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1262
|
https://f1000research.com/articles/10-842/v1
|
23 Aug 21
|
{
"type": "Research Article",
"title": "Glucose induced hepatic lipase expression and ApoB100/ApoAI ratio changes in cultured HepG2 cells in vitro",
"authors": [
"Minshan Hu"
],
"abstract": "Backgroundː Hepatic lipase (HL) plays a very important role in lipoprotein catabolism. The aim of this study was to measure both HL activity and ApoB100/ApoAI ratio changes in cell secretions by incubating HepG2 cells with various amounts of glucose. Methodsː HepG2 cells were cultured in low-, normal- or high-glucose Dulbecco's Modified Eagle Medium (DMEM) (1, 4.5 and 10g/L, respectively). HL activities were determined using the Hepatic Lipase Detection Kit (cat. no. A067) from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Levels of ApoAI and ApoB100 were measured with commercial sandwich enzyme-linked immunosorbent assay kits (cat#: H0123 and H0124) from ShangHai MEIXUAN Biological Science and Technology Ltd (Shanghai, China). Experiments were repeated six times for each assay. Resultsː Pearson’s correlation coefficient results showed that ApoB100 and ApoB100/ApoAI ratio have positive and significant correlations with HL activity, and ApoAI has a negative and significant correlation with HL activity. Conclusionsː Glucose may increase or decrease ApoB100/ApoAI ratio through upregulation or downregulation of hepatic lipase activity, which suggests a new regulatory pathway in lipoprotein catabolism. This finding may lead to novel therapeutic ways for diagnosis and treatment for coronary artery disease.",
"keywords": [
"ApoB100/ApoAI ratio",
"ApoB100",
"ApoAI",
"Hepatic lipase",
"Glucose"
],
"content": "Introduction\n\nAtherosclerotic coronary artery occlusion is the most frequent cause of coronary heart disease (CHD); numerous epidemiologic studies and randomized clinical trials have established that lipoprotein metabolism is a major contributor to CHD.1 Conventionally, it was thought that increases in plasma low-density lipoprotein cholesterol (LDL-C) and decreases in high-density lipoprotein cholesterol (HDL-C) were the major factors causing CHD.2 However, numerous studies have suggested that another factor in CHD risk might be the apolipoprotein B100/apolipoprotein AI (ApoB100/ApoAI) ratio.3–7 ApoB100 is a large surface protein present on low-density lipoprotein (LDL) and serves as a ligand for the LDL receptor, which facilitates its clearance from the plasma. Apolipoprotein AI (ApoAI) is the major protein constituent on high-density lipoprotein (HDL) and plays a central role in reverse cholesterol transport by stabilising the HDL particle, interacting with the ATP-binding cassette transporter I, activating lecithin cholesterol acyl transferase and acting as a ligand for the hepatic scavenger receptor.2\n\nHepatic lipase (HL) is synthesized and secreted by the liver, and is found extracellularly in the liver and in steroidogenic organs, primarily bound to proteoglycans. As a member of the lipase gene family, HL is a key enzyme catalyzing the hydrolysis of triglycerides (TG) and phospholipids (PLs), and it is involved in the remodeling of remnant LDL and HDL.8 It is also notable that HL facilitates the uptake of chylomicron remnant-like particles, not only as a lipolytic enzyme but also as a ligand, by bridging the lipoproteins to specific receptors or heparan sulphates on the hepatocytes.9\n\nHowever, it remains unclear whether HL is pro or anti-atherogenic in lipoprotein metabolism. Prior evidence indicates that it functions as a double-edged sword. On one hand, HL accelerates atherosclerosis by hydrolyzing large LDL particles to dense LDL lipoproteins. On the other hand, HL delays atherosclerosis by hydrolyzing HDL2 to smaller HDL3.10 In order to understand the mechanism of how HL modulates atherosclerosis at the molecular level, an in vitro cell assay model was built in the current study. HL activity and extracellular expression of ApoB100 and ApoAI were measured in cultured HepG2 cells. This research may provide the targets of many novel therapeutics and is an area with great potential for the prevention and treatment of CHD.\n\nIt has been shown that a high-carbohydrate (high-CHO) diet can reduce the risk of CHD. Further analysis found that this high-CHO diet interacted with different HL promoter polymorphisms to affect the ApoB100/ApoAI ratio instead of the HDL-C related ratios.6,7,11 In the current study, various amounts of glucose were used to stimulate the secretion of HL, ApoB100 and ApoAI in cultured HepG2 cells. It was hypothesized that the differential expression of HL could modulate ApoB100/ApoAI ratio in vitro.\n\n\nMethods\n\nHepG2 cells (American Type Culture Collection, ATCC, Rockville, MD, USA) were routinely cultured in DMEM + 10% FBS (contains 4.5 g/L glucose, normal glucose group) at 37°C in a 5% CO2 incubator up to 70% confluency. For ApoB100 and ApoAI expression assays, cell culture media that contained different concentrations of glucose (1 and 10g/L) were then added to the cultured cells in order to make the low glucose group and high glucose group besides the original normal glucose group. For the HL activity assay, 25U/ml heparin was added to the above low, normal and high glucose cell culture media used for ApoB100 and ApoAI expression assays to make the low, medium and high glucose groups for HL activity assay. All the cell groups then continued to be cultured for eight hours before the assays.\n\nThe culture media of HepG2 cells were collected. ApoB100 and ApoAI expression were measured with commercial sandwich enzyme-linked immunosorbent assay (ELISA) kits (cat. no. H0124 and H0123) from ShangHai MEIXUAN Biological Science and Technology Ltd (Shanghai, China). The microplate provided in this kit had been pre-coated with a monoclonal antibody specific for ApoB100 or ApoAI. Standards or samples were then pipetted into the microplate wells, and ApoB100 or ApoAI present in the samples or standards binds to antibodies adsorbed to the microplate wells. To quantitatively determine the amount of ApoB100 or ApoAI present in the samples, the horseradish peroxidase (HRP)-conjugated polyclonal antibody specific for ApoB100 or ApoAI was added to each well. The microplate was incubated for one hour, and then the wells were thoroughly washed to remove any unbound components. The substrate solutions A and B were respectively added to each well. After the enzyme (HRP) and substrate reacting over a short period, this reaction was stopped by addition of a sulphuric acid solution and the color change is measured at a wavelength of 450 nm. The proportion to amount of ApoB100 or ApoAI bound in the initial step develops in the color change. Color intensities were measured using a MK3 microplate reader (Thermo Fisher, MA, USA).\n\nHL activities were determined using the Lipoprotein Lipase (LPL)/Hepatic Lipase (HL) Detection Kit (cat. no. A067) from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). LPL and HL can catalyze the hydrolysis of triglyceride and the product of the reaction is glycerol and free fatty acid (FFA). The amount of free fatty acid can be determined in the presence of reagents from the kit and thus the activity of LPL and HL can be calculated. As a kind of glycoprotein, the activity of HL need not to be activated by apolipoprotein C-II or other ions and the activity will not be inhibited by protamine or high concentration of salt. According to this, the LPL activity and HL activity can be measured separately. The culture media of HepG2 cells were collected. Reagents I, III and VI from the kit were added, blend the mixture thoroughly for 2-5 minutes. The blending is not completed until the bottom of the tube appears to be cream color and the mixture will not separate immediately after stopping the blending. Centrifuge at 3,500 rpm for 10 minutes after the completion of blending. The result mixture should be layered clearly. Otherwise, the mixture should be re-blended and centrifuged again. Remove the supernatant and the solidified layer in middle with a glass pipette. Transfer the solution at the bottom layer with a glass pipette. The glass pipette should be washed 2-3 times with absolute ethanol followed by 2-3 times cleanings by reagent VI. Warm at 37°C for 1-2 minutes if turbidity is observed. Extract 1 ml solution obtained from step 5 and add chromogenic agent. The cuvettes should be washed by absolute ethanol followed by reagent VI. All methods are carried out with glass equipment. No plastic equipment is allowed. Color intensities were measured using a MK3 microplate reader (Thermo Fisher, MA, USA) at 550 nm with 0.5 cm path length. One enzyme activity unit is defined as 1μmol fatty acid generated with 1ml reaction volume within an hour.\n\nExperimental results were expressed as the mean ± standard deviation (SD). Statistical analyses were performed using one-way ANOVA to determine significant differences among groups. Pearson’s correlation coefficient was used to determine the correlation between the variables of ApoAI and HL, ApoB100 and HL, and ApoB100/ApoAI ratio and HL. IBM SPSS Statistics version 22 was used for data analysis.\n\n\nResults\n\nTo explore the impacts of glucose on ApoB100 and ApoAI secretion over different concentrations, HepG2 cells were exposed to low (1 g/L), medium (4.5 g/L) and high (10 g/L) concentrations of glucose. As shown in ELISA revealed that with the glucose concentration increase, ApoB100 concentrations were significantly increased (1 g/L < 4.5 g/L < 10 g/L), while ApoAI concentrations were significantly decreased (1 g/L > 4.5 g/L > 10 g/L). ApoB100/ApoAI ratios were significantly increased (1 g/L < 4.5 g/L < 10 g/L). ANOVA showed that the differences are significant (p < 0.001).21\n\nAs shown in Table 1 and Figure 1, significantly increased HL activities were observed with the glucose concentration increase (1 g/L < 4.5 g/L < 10 g/L). ANOVA showed that the differences are significant (p < 0.001).\n\nHepatic lipase activity, ApoB100, ApoAI and ApoB100/ApoAI ratio in HepG2 cell cultured in low, normal and high glucose concentration.\n\n** p < 0.05 for glucose concentration (4.5 g/L) vs. (1 g/L) or (10 g/L) vs. (1 g/L) (one-way ANOVA).\n\n## p < 0.05 for glucose concentration (1 g/L) vs. (4.5 g/L) or (10 g/L) vs. (4.5 g/L) (one-way ANOVA).\n\nHepatic lipase activity, ApoB100, ApoAI and ApoB100/ApoAI ratio in HepG2 cell cultured in low, normal and high glucose concentration.\n\nPearson’s correlation coefficient results showed positive and significant correlations between ApoB100 and HL activity (r = 0.782) (p < 0.001), and positive and significant correlations between ApoB100/ApoAI and HL activity (r = 0.890) (p < 0.001). Pearson’s correlation coefficient results also showed a negative and significant correlation between ApoAI and HL activity (r = −0.956) (p < 0.001) (Table 2).\n\nPearson’s correlation coefficients between ApoB100 and hepatic lipase activity, ApoAI and hepatic lipase activity, ApoB100/ApoAI ratio and hepatic lipase activity.\n\n\nDiscussion\n\nWhile studying the glucose-induced HL, ApoB100 and ApoAI expression in cultured HepG2 cell in vitro, in the culture media that contained a higher concentration of glucose, HL activities, ApoB100 concentrations and ApoB100/ApoAI ratios were found to be significantly increased, and ApoAI concentrations were significantly decreased. In the culture media that contained a lower concentration of glucose, however, HL activities, ApoB100 concentrations and ApoB100/ApoAI ratios were found to be significantly decreased, and ApoAI concentrations were significantly increased. This result is consistent with the author’s previous finding in an in vivo human cohort study that HL activity affects the ApoB100/ApoAI ratios instead of the HDL-C related ratios.6,7,11\n\nHowever, a high-CHO diet was found to have generally favorable effects on the ApoB100/ApoAI ratio, reducing CHD risk, in a previous human cohort study in vivo,6 while the higher concentration of glucose induced an undesirable ApoB100/ApoAI ratio change, increasing CHD risk, in the present in vitro study. We can reach a reasonable explanation to this seemingly contradictory data if we look at what is happening inside the body after the meal; the rich viscous fiber contained in the high-CHO diet we administered in our cohort study has been shown to significantly reduce postprandial glucose excursions,12–14 which means the cells inside the body were actually exposed to a lower level of glucose after the high-CHO diet. Thus, the results we obtained from the lower concentration of glucose in the HepG2 cell culture experiment in vitro should correspond to the results we obtained from the high-CHO diet experimental group in vivo.\n\nThis study supports our hypothesis that HL regulates lipoprotein metabolism by modulating ApoB100/ApoAI ratio. HL is considered to be a key kinase in lipoprotein metabolism, which regulates multiple cell functions, but its functions in cell signal transduction pathways are still not fully understood. This study aimed to elucidate the effect of HL on ApoB100/ApoAI ratio. HL may act as a double edge sword in the regulation of both ApoB100 and ApoAI functions in response to metabolic change such as glucose fluctuation, and the ultimate effects of HL can be measured by ApoB100/ApoAI ratio. It has already been shown in our current research that ApoB100/ApoAI ratio has positive and significant correlations with HL activity. Further studies are needed to determine the details of the series of events that take place in a cell.\n\nLipoproteins are spherical particles that carry lipids in the body. These particles contain both lipids and proteins. LDL and HDL are the two main types of lipoproteins. LDL delivers fat molecules to cells. A high LDL level means too much LDL cholesterol in the blood. This extra LDL, along with other substances, forms plaque which can build up in the arteries to form atherosclerosis. Plaque can be built up in the arteries, causing heart disease. HDL-C carries cholesterol from other parts of the body back to the liver. The liver then processes the cholesterol for excretion to reduce the risk of heart disease. It is well known that both LDL and HDL consist of heterogeneous particles of different size and density.15 ApoB100 is the primary protein in LDL and ApoAI is the primary protein in HDL. Normally, it is proteins instead of lipids which perform essential functions within organisms, including catalyzing metabolic reactions, providing structure to cells and organisms, and transporting molecules from one location to another. It is likely HL regulates lipoprotein metabolism by directly modulating their protein components like ApoB100 and ApoAI rather than their lipid components like triglycerides, phospholipids, and cholesterol molecules. Although previous in vivo studies have already indicated this,6,7,11 further in vitro studies are needed to prove it on a molecular level. The current study is the first to explore this issue in an in vitro cell culture system, and the result positively supports this hypothesis.\n\nFor many years, the ApoB100/ApoAI ratio rather than ApoB100 or ApoAI alone has been extensively reported as a risk factor of CHD.16–18 Atherosclerosis, the process involved in LDL oxidization within the walls of arteries, might be due to the more powerful function of ApoB100 to deliver lipids to the cells than ApoAI to transport lipids out of the cells and take them back to the liver. The dynamic equilibrium of these two proteins, which can be described in their ratios, is essential to our health.\n\nThis finding helps to explain why the existing clinical treatments based on the regulation of lipoproteins themselves cannot achieve the desired results in many clinical cases. For example, although statins have documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, the results of subsequent large prospective clinical trials using different types of statins clearly demonstrate that statins do not have a short-to-medium term effect on prevention of restenosis after successful conventional percutaneous transluminal coronary angioplasty.19 Current available data also indicate that increased HDL-C levels do not always correlate with enhanced HDL functions because HDL is highly heterogeneous and there are different HDL subpopulations.20\n\n\nConclusions\n\nIn conclusion, in vitro HepG2 cell culture revealed correlations between ApoB100, ApoAI, ApoB100/ApoAI ratios and HL activity. Higher amounts of glucose can induce significantly increased HL activity, ApoB100 levels and ApoB100/ApoAI ratio and significantly decreased ApoAI levels, while lower amounts of glucose can induce significantly decreased HL activity, ApoB100 levels, ApoB100/ApoAI ratio and significantly increased ApoAI levels. The result suggests a new and central cell signal transduction pathway in lipoprotein metabolism and might provide molecular targets for clinical diagnoses and treatments of CHD.\n\n\nData availability\n\nHarvard Dataverse: Replication Data for: Glucose induced hepatic lipase expression and ApoB100/ApoAI ratio changes in cultured HepG2 cells in vitro, https://doi.org/10.7910/DVN/CUBA3F.21\n\nThis project contains the following underlying data:\n\n• dataset–Glucose Induced ApoAI-ApoB100-HL.tab\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\nValanti EK, Dalakoura-Karagkouni K, Siasos G, et al.: Advances in biological therapies for dyslipidemias and atherosclerosis. Metabolism. 2021 Mar; 116: 154461. Epub 2020/12/09. PubMed Abstract | Publisher Full Text\n\nGerman C, Shapiro M: Assessing Atherosclerotic Cardiovascular Disease Risk with Advanced Lipid Testing: State of the Science. Eur Cardiol. 2020; 15: e56. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang X, Wang Z, Li B, et al.: Prognosis evaluation of universal acute coronary syndrome: the interplay between SYNTAX score and ApoB/ApoA1. BMC Cardiovasc Disord. 2020; 20(1): 293. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSong Y, Yang Y, Zhang J, et al.: The apoB100/apoAI ratio is independently associated with the severity of coronary heart disease: a cross sectional study in patients undergoing coronary angiography. Lipids Health Dis. 2015; 14: 150. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu L, Lu Z, Zhu L, et al.: Lipoprotein ratios are better than conventional lipid parameters in predicting coronary heart disease in Chinese Han people. Kardiol Pol. 2015; 73(10): 931–8. PubMed Abstract | Publisher Full Text\n\nHu M, Li Z, Fang D: A high-carbohydrate diet effects on the A allele of hepatic lipase polymorphism on the apoB100/apoAI ratio in young Chinese males. Adv Clin Exp Med: official organ Wroclaw Medical University. 2012; 21(6): 751–7. PubMed Abstract\n\nHu M, Li Z, Fang D: A high carbohydrate diet induces the beneficial effect of the CC genotype of hepatic lipase C-514T polymorphism on the apoB100/apoAI ratio only in young Chinese males. Scand J Clin Lab Invest. 2012; 72(7): 563–9. PubMed Abstract | Publisher Full Text\n\nKobayashi J, Miyashita K, Nakajima K, et al.: Hepatic Lipase: a Comprehensive View of its Role on Plasma Lipid and Lipoprotein Metabolism. J Atheroscler Thromb. 2015; 22(10): 1001–11. PubMed Abstract | Publisher Full Text\n\nDiard P, Malewiak M, Lagrange D, et al.: Hepatic lipase may act as a ligand in the uptake of artificial chylomicron remnant-like particles by isolated rat hepatocytes. Biochem J. 1994: 889–94. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZambon A, Deeb S, Pauletto P, et al.: Hepatic lipase: a marker for cardiovascular disease risk and response to therapy. Curr Opin Lipidol. 2003; 14(2): 179–89. PubMed Abstract | Publisher Full Text\n\nHu MS, Li ZK, Fang DZ: The association study of the LIPC -250g/A polymorphism and high-carbohydrate/low-fat diet induced serum lipid and apolipoprotein concentration changes in healthy youth. Sichuan Da Xue Xue Bao Yi Xue Ban. 2013 Sep; 44(5): 727–30, 35 Epub 2013/12/12. PubMed Abstract\n\nJenkins AL, Morgan LM, Bishop J, et al.: Randomized clinical trial in healthy individuals on the effect of viscous fiber blend on glucose tolerance when incorporated in capsules or into the carbohydrate or fat component of the meal. J Am Coll Nutr. 2014; 33(5): 400–405. Epub 2014/10/11. PubMed Abstract | Publisher Full Text\n\nWolever TMS, Jenkins AL, Yang J, et al.: An Optimized, Slowly Digested Savory Cluster Reduced Postprandial Glucose and Insulin Responses in Healthy Human Subjects. Curr Dev Nutr. 2019 Mar; 3(3): nzz006. Epub 2019/03/19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu X, Lin J, Song Y, et al.: A high-carbohydrate diet lowered blood pressure in healthy Chinese male adolescents. Biosci Trends. 2014 Apr; 8(2): 132–7. Epub 2014/05/13. PubMed Abstract | Publisher Full Text\n\nHirano T: Pathophysiology of Diabetic Dyslipidemia. J Atheroscler Thromb. 2018; 25(9): 771–82. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcQueen M, Hawken S, Wang X, et al.: Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet (London, England). 2008; 372(9634): 224–33. PubMed Abstract | Publisher Full Text\n\nGalal H, Samir A, Shehata M: Assessment of apolipoprotein B/apolipoprotein A-I ratio in non-ST segment elevation acute coronary syndrome patients. Egypt Heart J: (EHJ) : official bulletin of the Egyptian Society of Cardiology. 2020; 72(1): 27. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnderson T, Grégoire J, Hegele R, et al.: 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013; 29(2): 151–67. PubMed Abstract | Publisher Full Text\n\nHorlitz M, Sigwart U, Niebauer J: Fighting restenosis after coronary angioplasty: contemporary and future treatment options. Int J Cardiol. 2002; 83(3): 199–205. Publisher Full Text\n\nEscolà-Gil J, Cedó L, Blanco-Vaca F: High-density lipoprotein cholesterol targeting for novel drug discovery: where have we gone wrong? Expert Opin Drug Discov. 2014; 9(2): 119–24. PubMed Abstract | Publisher Full Text\n\nHu M: Replication Data for: Glucose induced hepatic lipase expression and ApoB100/ApoAI ratio changes in cultured HepG2 cells in vitro."
}
|
[
{
"id": "96276",
"date": "02 Nov 2021",
"name": "Anne Tailleux",
"expertise": [
"Reviewer Expertise Cardiometabolic diseases",
"bile acids and their receptors",
"NAFLD"
],
"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:\nThe objective of the study was to analyse the impact of glucose on hepatic lipase activity, ApoB100 and ApoA1 secretion in hepatocytes. The author performed a single in vitro study, using a well-documented human hepatocyte cell line, namely HepG2, incubated with different levels of glucose. HL activity, ApoB100 and ApoA1 were determined in the supernatant of the cell culture.\nThe argument of why to watch the impact of glucose on HL/Apos parameters is not clearly stated in the introduction.\n\nA number of details are missing for the understanding of the methodological part.\n\n\"Experiments were repeated six times for each assay\" is stated in the Abstract. Is it the cell experiment or the dosages of HL, ApoB100 and ApoA1 that have been performed 6 times? This point should be clarified in the methods section.\n\nWhat is the duration of incubation for the cell experiment? Are the results time-dependant? A kinetic study should be informative.\n\nMethods section: HL activity is expressed as 1 µmol FA with 1 ml reaction volume. In Table 1, HL is expressed as U/mg. The author should clarify.\n\nStatistical analysis: the author used a one-way ANOVA test to see differences between groups by global analysis. What is the post-hoc test used?\nTable 1 and Figure 1 represent exactly the same information and are redundant. The author should choose. If the figure is chosen, the unit of abscise should be added and the legend of the figure completed.\n\nThe author has shown an association between HL activity and ApoB100/ApoA1, and they conclude that HL is a factor modifying Apos. What are the arguments to say that it's not the opposite?\n\nHepG2 is a cancer cell line. Cautions should be taken before extending the results obtained with a cancer line to hepatocytes. This point should be introduced in a \"limitation of the study\" paragraph in the discussion.\n\nApoB100 is synthetised exclusively by the liver, in contrast to ApoA1 is synthetised by the liver and the intestine. However, the author makes a parallel between the results obtained with a hepatocyte cell line and what appends in vivo in the circulation of patients. This point should be modified.\n\nIn the discussion, the author states that \"HL regulates lipoprotein metabolisms by directly modulating… rather than lipid content like triglyceride\". An HL is a lipase, it is very surprising! The author should modulate.\n\nEven if the author does not look for the molecular mechanisms underlying the association between HL and Apos, in the presence of glucose, they could at least speculate and state their hypothesis. Does the HL act via the FFA released that could modify gene expression of the Apos? Do Apos physically interact with HL? How could glucose modify the process? Others?\n\nWhat is the phenotype of mice knock-out for HL (whole body or hepato-specific)? Do they have an altered concentration of circulating ApoB and ApoA1?\n\nThe discussion is a kind of juxtaposition of paragraphs without a narrative line. It is largely redundant and could be better structured.\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? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7628",
"date": "10 Jan 2022",
"name": "Minshan Hu",
"role": "Author Response",
"response": "Dear Dr. Tailleux, I appreciate the time and effort that you have dedicated to providing your valuable feedback on my manuscript. I am grateful to you for your insightful comments on my paper. I have been able to incorporate changes to reflect most of the suggestions provided by you. I have highlighted the changes within the manuscript. Here is a point-by-point response to your comments and concerns. Comment 1: The argument of why to watch the impact of glucose on HL/Apos parameters is not clearly stated in the introduction. Response: I agree with this. Although the impact of HL on ApoB100/ApoAI ratio changes has been shown in a previous human cohort study in vivo, we have not yet obtained enough solid evidence that HL contributes to ApoB100/ApoAI ratio changes in vitro. I have incorporated your suggestion throughout the manuscript by eliminating HL data, and limiting the current report to only observe the ApoB100/ApoAI ratio changes in response to glucose concentration changes. Comment 2: A number of details are missing for the understanding of the methodological part. Response: You have raised an important point here. The changes have been made, please refer to the response to comment 5. Comment 3: \"Experiments were repeated six times for each assay\" is stated in the Abstract. Is it the cell experiment or the dosages of HL, ApoB100 and ApoA1 that have been performed 6 times? This point should be clarified in the methods section. Response: For those parameter measurements (HL, ApoB100 or ApoAI), six individual wells of cells were used for each concentration of glucose (please refer to Data availability in manuscript). Comment 4: What is the duration of incubation for the cell experiment? Are the results time-dependant? A kinetic study should be informative. Response: The experimental design of the duration of incubation for the cell experiment was according to PMID: 18758746. After cells reach 70% confluency, all the cell groups were then continued to be cultured for eight hours before the assays. Thank you for pointing out that it is better to measure those parameters in a time-dependent manner. I agree with this comment. Therefore, I will conduct those experiments in the ongoing research work. Comment 5: Methods section: HL activity is expressed as 1 µmol FA with 1 ml reaction volume. In Table 1, HL is expressed as U/mg. The author should clarify. Response: Thank you for pointing this out. I agree with this comment. Enzyme activity is the amount of substrate converted by the enzyme in moles per unit time. It measures the amount of active enzyme present in a mixture at a given time. On the other hand, specific activity is the activity of the enzyme per mg of total protein. Protein content was quantified by Coomassie Brilliant Blue assay, using bovine serum albumin (BioRad) as standard. Although specific HL activity was calculated, total protein measurement was missing from the Methods section. Comment 6: Statistical analysis: the author used a one-way ANOVA test to see differences between groups by global analysis. What is the post-hoc test used? Response: The post-hoc test is used to dive in and look for differences between groups testing each possible pair of groups. Comment 7: Table 1 and Figure 1 represent exactly the same information and are redundant. The author should choose. If the figure is chosen, the unit of abscise should be added and the legend of the figure completed. Response: Thank you for pointing this out. I agree with this comment. Figure 1 has been deleted, and only Table 1 is kept and revised. Comment 8: The author has shown an association between HL activity and ApoB100/ApoA1, and they conclude that HL is a factor modifying Apos. What are the arguments to say that it's not the opposite? Response: Thank you for pointing this out. The current experimental data are far less enough to prove the association, so we only reach the conclusion of a higher concentration of glucose-induced an undesirable ApoB100/ApoAI ratio change in the revised version and rule out all the data related to HL. Comment 9: HepG2 is a cancer cell line. Cautions should be taken before extending the results obtained with a cancer line to hepatocytes. This point should be introduced in a \"limitation of the study\" paragraph in the discussion. Response: Thank you for pointing this out. Cancer cell lines and primary cells do behave differently in some aspects, particularly in cell proliferation. HepG2 is used in this research by referring to numerous other similar published work related to hepatic cell signal transduction pathways (PMID: 30466006, PMID: 29886733, PMID: 31853220, etc.). But certainly, I am going to check this result in hepatocytes in future research. Comment 10: ApoB100 is synthetized exclusively by the liver, in contrast to ApoA1 is synthetized by the liver and the intestine. However, the author makes a parallel between the results obtained with a hepatocyte cell line and what appends in vivo in the circulation of patients. This point should be modified. Response: Thank you for this suggestion. However, the hypothesis of this study is that a major contributor to coronary heart disease is the dynamic equilibrium of apolipoproteins which deliver lipids to the cells and transport lipids out of the cells and take them back to the liver. Considering there are many other apolipoproteins involved in this “to the cells” and “back to the liver” process, the main event that happens in the liver is what I am exploring. And thank you for pointing this out, regarding the dynamic equilibrium, other apolipoproteins secreted from the entire body should be studied in the future. Comment 11: In the discussion, the author states that \"HL regulates lipoprotein metabolisms by directly modulating… rather than lipid content like triglyceride\". An HL is a lipase, it is very surprising! The author should modulate. Response: Thank you for pointing this out. The current experimental data are far less enough to prove this. So I have ruled out all the research work related to HL in the revised version. Comment 12: Even if the author does not look for the molecular mechanisms underlying the association between HL and Apos, in the presence of glucose, they could at least speculate and state their hypothesis. Does the HL act via the FFA released that could modify gene expression of the Apos? Do Apos physically interact with HL? How could glucose modify the process? Others? Response: Thank you for pointing this out. The current experimental data are far less enough to prove these and I am going to explore these in the future. Comment 13: What is the phenotype of mice knock-out for HL (whole body or hepato-specific)? Do they have an altered concentration of circulating ApoB and ApoA1? Response: The in vivo human cohort studies were conducted instead of mice. Comment 14: The discussion is a kind of juxtaposition of paragraphs without a narrative line. It is largely redundant and could be better structured. Response: Thank you for this suggestion. I have restructured as suggested."
}
]
},
{
"id": "98246",
"date": "26 Nov 2021",
"name": "Li Lin",
"expertise": [
"Reviewer Expertise Prevention",
"treatment and pathophysiological study of senile and chronic 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, Minshan Hu reported that glucose may increase or decrease ApoB100/ApoAI ratio through up-and down-regulation of hepatic lipase activity, which suggests a new regulatory pathway in lipoprotein catabolism.\nThe observations in this work are interesting with some merits. However, there are some major issues that remain to be addressed.\n\nThe overall design of the experiment is too simple, it is best to complement the relevant mechanism of the experiment.\n\nThe statistics and statistical identification (Table 1) in the MS are not clearly described. In addition, the statistical drawing of Fig.1 is not standardized.\n\nThe MS was not very carefully prepared in organization and writing, for example, the discussion should focus on the experimental results and analyze the reasons and possible mechanisms.\n\nAn English language edit is required.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": "7629",
"date": "10 Jan 2022",
"name": "Minshan Hu",
"role": "Author Response",
"response": "Dear Dr. Lin, I appreciate the time and effort that you have dedicated to providing your valuable feedback on my manuscript. I am grateful to you for your insightful comments on my paper. I have been able to incorporate changes to reflect most of the suggestions provided by you. I have highlighted the changes within the manuscript. Here is a point-by-point response to your comments and concerns. Comment 1: The overall design of the experiment is too simple, it is best to complement the relevant mechanism of the experiment. Response: Thank you for pointing this out. The current experimental data are far less enough to prove the association, so we only reach the conclusion of a higher concentration of glucose-induced an undesirable ApoB100/ApoAI ratio change in the revised version and rule out all the data related to HL. Comment 2: The statistics and statistical identification (Table 1) in the MS are not clearly described. In addition, the statistical drawing of Fig.1 is not standardized. Response: Thank you for pointing this out. Figure 1 has been deleted, and only Table 1 is kept in the revised version. Comment 3: The MS was not very carefully prepared in organization and writing, for example, the discussion should focus on the experimental results and analyze the reasons and possible mechanisms. Response: Thank you for pointing this out. The manuscript can be better prepared when more experimental results will be obtained in the future. Comment 4: An English language edit is required. Response: Thank you for this suggestion. English language has been edited."
}
]
}
] | 1
|
https://f1000research.com/articles/10-842
|
https://f1000research.com/articles/10-1086/v1
|
26 Oct 21
|
{
"type": "Research Article",
"title": "Comparison of accidental pediatric scald burns in a tertiary care center: hot cauldron burns versus accidental spill burns",
"authors": [
"Kiran Kishor Nakarmi",
"Bishnu Deep Pathak",
"Dhan Shrestha",
"Pravash Budhathoki",
"Shankar Man Rai",
"Kiran Kishor Nakarmi",
"Dhan Shrestha",
"Pravash Budhathoki",
"Shankar Man Rai"
],
"abstract": "Background: Scald burns result from exposure to high-temperature fluids and are more common in the pediatric age group. They occur mainly by two mechanisms: (i) spill and (ii) immersion (hot cauldron) burns. These two patterns differ in clinical characteristics and outcomes. Scalds cause significant morbidity and mortality in children. The objective of this study was to compare accidental spill burns and hot cauldron burns in a hospital setting. Methods: An analytical cross-sectional study was conducted by reviewing the secondary data of scald cases admitted during the years 2019 and 2020 in a burn-dedicated tertiary care center. Total population sampling was adopted. Data analysis was done partly using SPSS, version-23, and Stata-15. Mann Whitney U-test and Chi-square/Fisher's exact test were done appropriately to find associations between different variables. Regression analysis was performed taking mortality events as the outcome of interest. Results: Out of 108 scald cases, 43 (39.8%) had hot cauldron burns and 65 (60.2%) had accidental spill burns. Overall mortality was 16 (14.8%), out of which hot cauldron burns and accidental spill burns comprised 12 (75.0%) and 4 (25.0%), respectively. Multinomial logistic regression analysis showed the type of scald, age, and Baux score found to be associated with mortality. Every one-year increment in age had a 29% lower odds of occurrence of mortality event (adjusted odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50-0.99, p=0.042). Likewise, every one-point increment in Baux score was associated with 19% higher odds of mortality (adjusted OR, 1.190; 95% CI, 1.08-1.32; p<0.001). Conclusions: Accidental spill burns were more common but mortality was significantly higher for hot cauldron burns. The majority of burn injuries occurred inside the kitchen emphasizing appropriate parental precautions. The risk of mortality was significantly higher in burn events occurring outside the house, and burns involving back, buttocks, perineum, and lower extremities.",
"keywords": [
"accidental",
"pediatric",
"burns",
"immersion"
],
"content": "Introduction\n\nScald burns are the most common types of burn injuries in children throughout the world.1,2 These injuries are the leading cause of morbidity and mortality in the pediatric population.3,4 They have long-term physical, psychological and economic impacts on the patients and their families. The majority of scald injuries occur at home and most of them are accidental and preventable.5–7\n\nScalds result from exposure to hot liquids or steam. They occur mainly by two mechanisms: (i) spill and (ii) immersion burns.8–10 Accidental spill burns are due to spillage of hot liquid such as boiling water, tea, milk, oil, soup, etc. These burns usually happen if a child gets in the way of an adult carrying hot fluids or accidentally play with the utensils filled with hot liquid and spill over their body. Immersion burns take place when children fall or put their hands/feet into a vessel containing hot liquid such as bathtub, tea/coffee pots, hot cauldrons, etc.3,6,11–14 Past studies have shown that the patterns of these two scalds differ widely for different age groups, gender, and body parts involved, with differences in hospital stay and outcomes secondary to extent of burns.6,15–17\n\nThe study of different types of scalds can help to control or reduce the predisposing factors and ultimately help in formulating plans and strategies for prevention. This study aimed to compare accidental spill and immersion (hot cauldron) scald burns in a tertiary care center and assess morbidity and mortality caused by them.\n\n\nMethods\n\nThe study was conducted in the tertiary care center Kirtipur Hospital, Kathmandu, Nepal. It is a national referral center for the management of burn injuries. This hospital has 100 beds in total. Out of these, 32 beds are allocated for burn cases only; of which eight are in Burn Intensive Care Unit (BICU). It takes care of the whole spectrum of burn cases from acute care to the full range of reconstructive services and rehabilitation.\n\nThis was a single-center, analytical, cross-sectional study carried out by reviewing the secondary data of scald burn cases admitted during two years (2019 and 2020). Out of all scalds, only pediatric cases (age < 18 years) were included in our study. Secondary data was collected from hospital records maintained in electronic form which included all of the acute scald cases admitted to the Plastic Surgery Ward and BICU. Scald cases managed on an outpatient basis were excluded from the study. Total population sampling was used. Those cases with incomplete records were excluded.\n\nThe data extracted from the patients' electronic records and stored in our database included demographic information like age, gender, and address of residence. All the immersion injury cases presented to our center had occurred due to falling into cauldrons filled with boiling water containing shredded straw and husk to feed cattle, which is commonly used in Nepal. Spill burns occurred due to spillage of hot liquids (boiling water, tea, coffee, milk, and oil). The mechanism of scalds was categorized into two broad groups: hot cauldron burns (HCB) and accidental spill burns (ASB). Data related to burn injury included type (mechanisms) of scalds, place of burn, pre-hospital intravenous fluid use, presence of infection at presentation, total body surface area, and body parts involved. Likewise, data of in-hospital interventions such as blood transfusion, escharotomy, necrosectomy, tangential excision, second excision, use of graft and/or flap, amputation were also taken. Outcome variables like duration of hospital stay and mortality were also noted.\n\nSince we were collecting data from patients’ electronic records, there was possibility that the hospital staffs might have made errors during data entry in the records. This could give rise to information bias in our study. To reduce it to minimum, we cross-checked every information with patients’ admission files stored in hospital administratin section itself. Next, all the eligible cases were included in the study. So, there was minimal chance of selection bias as well.\n\nEthical approval was taken from the Institutional Review Committee (IRC no. 006-2021), phect-NEPAL. Before conducting the study, permission was taken from the Department of Burns, Plastic and Reconstructive Surgery. The anonymity of patient information was well-maintained and thus patient consent was waived by the ethical review board.\n\nShapiro-Wilk W test showed that our continuous variables were distributed non-normally, so median and inter-quartile range (IQR) were calculated. Among categorical variables, Chi-square/Fisher’s exact test was applied to check the association between independent and dependent variables. Frequency and percentages were presented appropriately in tables. The level of significance was taken as p < 0.05, with a 95% confidence interval (CI) considering a 5% standard error. The analysis was run partly using IBM SPSS version 23, and Stata version 15.\n\nLogistic regression\n\nThe dependent variable was mortality outcome, while the rest of the other variables affecting mortality were independent variables. For regression analysis, the outcome of interest as mortality event was taken and those who died in course of treatment were labeled as 1, and those who survived were labeled as 0. Initially binary logistic regression was run to see the effect of individual variables in mortality outcome. Only those variables which were found to be associated in Chi-square/Fisher’s exact test and significant continuous variables (age, length of hospital stay, and Baux score) were taken for logistic regression analysis. Later, multinomial logistic regression analysis was performed to check the exact effect of independent variables adjusting to the rest of the variables to check and nullify the confounding effect of different variables evaluated. Unadjusted odds ratio (OR) for binary logistic regression and adjusted OR for multinomial logistic regression analysis were presented with 95% CIs. The pseudo R2 value for multinomial logistic regression analysis was 0.5367, indicating that our model predicts a similar outcome in about 54% of observations. Multicollinearity across the studied variables was automatically tested by STATA software and no observed variables were omitted across selected variables for multinomial logistic regression analysis.\n\n\nResults\n\nA total of 120 pediatric patients with scald burns were admitted during the two-year period. Out of them, 12 were excluded from our study due to their incomplete records. Finally, 108 cases were analyzed.23 Demographic and clinical characteristics of the patients are shown in Table 1. The median age of the patients was 2.8 (IQR = 1.6-4.0) years. In total, 61 (56.5%) of them were male and 47 (43.5%) were female. The majority of the burn injuries occurred in the kitchen (57.4%) and most of the patients were from the Low mountain region (60.2%) of Nepal.\n\nOverall, 43 (39.8%) had HCB and 65 (60.2%) had ASB. There was no significant difference in age, gender, place of burns, and pre-hospital intravenous fluid use in the two groups of scald patients. Baux score was higher in HCB (17.5, IQR = 14.0-27.0) but the median body surface area of burns was equal (15%) in both the groups. In total, 13 cases (12.0%) had an infection at presentation, which was higher in HCB (53.8%) than in ASB (46.2%). Neither of them were statistically significant.\n\nThe most commonly involved body parts were lower extremities (55.6%) followed by upper extremities (49.1%) and hands (40.7%). Of all the lower extremities burns, 36 (60.0%) were from ASB, and 24 (40.0%) were from HCB. None of these were statistically significant.\n\nTangential excision was performed in 52 (48.1%) patients, of which 34 (65.4%) and 18 (34.6%) belonged to ASB and HCB groups, respectively. Cases requiring the second excision (7.4%) were equally distributed in both groups (50.0%). Only two patients required flap and amputation and they were from the HCB group.\n\nOverall mortality was 16 (14.8%). Out of total deaths, 12 (75%) were from HCB and four (25%) from the ASB group. This was statistically significant (p = 0.002). Requirement of in-hospital blood transfusion was significantly higher (p = 0.030) in HCB (57.1%) than ASB cases (42.9%). The median duration of hospital stay in both groups was nine days (IQR in HCB: 5.0-13.0, ASB: 3.0-14.0).\n\nA significant association was seen between the dependent variable mortality and type of scalds (p = 0.002), place where burn injury took place (p = 0.010), and involvement of body parts like back (p = 0.015), buttock (0.001), perineum (p = 0.026) and lower extremities (0.005) (Table 2).\n\nBinary and multinomial logistic regression analysis was run to check association across variables showing significant association by Chi-square/Fisher’s exact test and continuous variables namely, patient’s age, length of hospital stay, and Baux score (Table 3). Binary logistic regression showed higher mortality in HCB in comparison to ASB type of scald. Similarly, burns occurring outside the house had a higher association with mortality. Involvement of the back, buttock, perineum, and lower extremities was found to be associated with higher odds of mortality. However, adjusting independent variables and continuous variables (age, Baux score, length of stay) showed the only type of scald, age, and Baux score found to be associated with mortality. Every one-year increment in age has a 29.0% lower odds of occurrence of mortality event (adjusted OR, 0.71; 95% CI, 0.50-0.99, p = 0.042). Likewise, every one-point increment in Baux score was associated with 19% higher odds of mortality (adjusted OR, 1.19; 95% CI, 1.08-1.32; p < 0.001).\n\n\nDiscussion\n\nIn our study, HCB and ASB accounted for 39.8% and 60.2% of total cases respectively. Although there are numeric differences across the two groups in terms of demographic and clinical profile, statistical significance exists in mortality and in-hospital blood transfusion only. Overall mortality was 16 (14.8%), out of which 12 (75%) were from HCB and 4 (25%) from the ASB group. Blood transfusion was required more in HCB cases (57.1%) than in ASB cases (42.9%). Mortality was higher in male gender (16.4%), burns outside the house (40.0%), body parts involving head and neck (18.2%), chest (15.0%), back (29.0%), abdomen (22.2%), buttocks (34.5%), perineum (44.4%), lower extremities (23.3%) and those who underwent escharotomy (16.7%) and necrosectomy (50.0%). Out of these, burns outside house (p = 0.010), involvement of buttocks (p = 0.001), back (p = 0.015), perineum (p = 0.026) and lower extremities (p = 0.005) were statistically significant.\n\nA study in India18 reported the mortality in pediatric scald burns to be 3.1% which is lower compared to our number (14.8%). The plausible explanation for these differences is the difference in the site of study, sample size, and duration of the study. Another reason could be because our center is a national referral center for burns, so it is likely that more complicated and extensive cases are being referred here. Another study in Kashmir, India19 showed mortality from scalds to be 10.7% which is comparable to our findings. The most common place of burn event in our study was a kitchen (57.4%) which is comparable to a study (64.7%) done by Riedlinger DI et al. Similarly, grafting was done in 41.2% of patients which also corresponds to our study (46.3%).5 Another study6 depicted the incidence of accidental immersion and spill burns as 5.4% and 81.4%, respectively, which differs from our findings where immersion (hot cauldron) and spill burns comprise 39.8% and 60.2%, respectively. Similarly, a Turkish study3 showed that the most frequent cause of burn was scalding from spillage of hot water (59.7%) followed by bath scalding (i.e. immersion injury) accounting for 26% of cases. This is in line with the percentage of spill burns in our case. Likewise, in Japan, immersion burn (59.3%) was reported to be higher than spill burns (40.7%).16 This could be due to the provision of the bathtub in developed countries like Japan where there is a high chance of children climbing up and falling into bathtubs.\n\nThe most commonly involved body parts were lower limbs (55.6%) and upper limbs (49.1%) in our study. This finding contradicts a study by Drago DA et al,6 where the upper torso (25.3%) and upper limbs (24.1%) were maximally involved. A Japanese study16 revealed that the most common sites of immersion injury were trunk and legs (80%) followed by arms, and those of spill burns were trunk (91.7%) followed by head/neck and arms. In our case, the most common body parts involved were lower followed by upper extremities. The same study showed the average body surface area of scald as 11.3% which is slightly lower than ours (15.0%). Immersion-related burns were more likely to be located on the lower half of the body involving buttocks, thighs, legs, and feet in a French study.17 Another also found out that most scalds occurred on the upper limbs.20 These discrepancies could be due to different sample sizes and sites of study. The mean total body surface area reported in a study from Arizona21 was 8.0% which is much lower than ours (15.0%). The difference could be due to our center being a referral center where complicated burn cases are being referred from all over the country. However, the mean length of hospital stay in this study21 (8 days) is similar to our study (9 days).\n\nIn a study from Ontario,15 Children with spill burns had a shorter average length of hospital stay (10.8 days) compared to those involved in bathtub immersion burns (18.3 days). In our study, the median duration of hospital stay was equal in both the groups of scalds (nine days) though it was not statistically significant. Likewise, in the same study, the mean age in both scald groups was 1.8 years whereas, in our setting, the median age in HCB and ASB were 3.0 and 2.5 years, respectively. A study from Beijing22 showed that the scald burns most commonly occurred in the kitchen which supports our result.\n\nThere are some limitations of this study that need to be mentioned. The number of cases was lower than expected because of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Lack of complete data also excluded a significant portion of cases from the study. The data also fails to analyze the economic status of children which could make them susceptible not only to a certain type of scald burn but also limits the access to first aid and primary care, hence affecting the outcome. Moreover, this is a single-center study over a short period of time so, the results may not be applicable to the whole country. For that purpose, multi-center studies conducted over a longer duration are recommended.\n\n\nConclusions\n\nASB was more common in our setting but mortality was higher in HCB. The latter were more likely to require an in-hospital blood transfusion. Most of the scalds occurred in the kitchen so parental precautions are necessary. There were no other significant differences between these two groups. Overall in-hospital deaths were higher than in other countries. The risk of mortality was significantly higher in burn events occurring outside, and those involving the back, buttocks, perineum, and lower extremities. So, special focus should be given to these factors during management.\n\n\nData availability\n\nFigshare: Comparison of Accidental Pediatric Scald Burns in a Tertiary Care Center: Hot Cauldron Burns versus Accidental Spill Burns.sav. http://doi.org/10.6084/m9.figshare.16583501.23\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nKhan T, Wani A, Darzi M, et al.: Epidemiology of burn patients in a tertiary care hospital in Kashmir: A prospective study. Indian J Burn. 2014 [cited 2021 Jun 27]; 22(1): 98. Publisher Full Text Reference Source\n\nAllasio D, Fischer H: Immersion scald burns and the ability of young children to climb into a bathtub. Pediatrics. 2005 May [cited 2021 Jun 19]; 115(5): 1419–21. Publisher Full Text PubMed Abstract | Reference Source\n\nSakallioǧlu AE, Başaran Ö, Tarim A, et al.: Burns in Turkish children and adolescents: Nine years of experience. Burns. 2007 Feb [cited 2021 Jun 18]; 33(1): 46–51. PubMed Abstract | Publisher Full Text Reference Source\n\nChalya PL, Mabula JB, Dass RM, et al.: Pattern of childhood burn injuries and their management outcome at Bugando Medical Centre in Northwestern Tanzania. BMC Res Notes. 2011 [cited 2021 Jun 19]; 4. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nRiedlinger DI, Jennings PA, Edgar DW, et al.: Scald burns in children aged 14 and younger in Australia and New Zealand - An analysis based on the Burn Registry of Australia and New Zealand (BRANZ). Burns. 2015 May 1 [cited 2021 Jun 18]; 41(3): 462–8. PubMed Abstract | Publisher Full Text Reference Source\n\nDrago DA: Kitchen scalds and thermal burns in children five years and younger. Pediatrics. 2005 Jan [cited 2021 Jun 18]; 115(1): 10–6. PubMed Abstract | Publisher Full Text Reference Source\n\nShrestha SR: Burn injuries in pediatric population. JNMA J Nepal Med Assoc. 2006 Jul 1 [cited 2021 Jun 27]; 45(163): 300–5. PubMed Abstract Reference Source\n\nThermal Burns: Overview, Pathophysiology, Quantifying Burn Severity.[cited 2021 Jun 18].Reference Source\n\nHettiaratchy S, Dziewulski P: Pathophysiology and types of burns. BMJ. 2004 Jun 12 [cited 2021 Jun 18]; 328(7453): 1427–1429. PubMed Abstract | Publisher Full Text | Free Full Text\n\nScald - an overview|ScienceDirect Topics:[cited 2021 Jun 19].Reference Source\n\nMukerji G, Chamania S, Patidar GP, et al.: Epidemiology of paediatric burns in Indore, India. Burns. 2001 [cited 2021 Jun 18]; 27(1): 33–8. PubMed Abstract | Publisher Full Text Reference Source\n\nShields WC, McDonald EM, Pfisterer K, et al.: Scald burns in children under 3 years: An analysis of NEISS narratives to inform a scald burn prevention program. Inj Prev. 2015 Oct 1 [cited 2021 Jun 18]; 21(5): 296–300. PubMed Abstract | Publisher Full Text Reference Source\n\nChapman JC, Sarhadi NS, Watson ACH: Declining incidence of paediatric burns in Scotland: a review of 1114 children with burns treated as inpatients and outpatients in a regional centre. Burns. 1994 [cited 2021 Jun 18]; Vol. 20: p. 106–10. Publisher Full Text Reference Source\n\nCauldron - Wikipedia:[cited 2021 Jun 18].Reference Source\n\nRay JG: Burns in young children: a study of the mechanism of burns in children aged 5 years and under in the Hamilton, Ontario burn Unit. Burns. 1995 [cited 2021 Jun 18]; 21(6): 463–6. PubMed Abstract | Publisher Full Text Reference Source\n\nFukunishi K, Takahashi H, Kitagishi H, et al.: Epidemiology of childhood burns in the Critical Care Medical Center of Kinki University Hospital in Osaka, Japan. Burns. 2000 Aug 1 [cited 2021 Jun 18]; 26(5): 465–9. PubMed Abstract | Publisher Full Text Reference Source\n\nMercier C, Blond MH: Epidemiological survey of childhood burn injuries in France. Burns. 1996 [cited 2021 Jun 18]; 22(1): 29–34. PubMed Abstract | Publisher Full Text Reference Source\n\nKumar P, Chirayil PT, Chittoria R: Ten years epidemiological study of paediatric burns in Manipal, India. Burns. 2000 May 1 [cited 2021 Jun 18]; 26(3): 261–4. PubMed Abstract | Publisher Full Text Reference Source\n\nKhan T, Wani A, Darzi M, et al.: Epidemiology of burn patients in a tertiary care hospital in Kashmir: A prospective study. Indian J Burn. 2014 [cited 2021 Jun 19]; 22(1): 98. Publisher Full Text Reference Source\n\nZhu L, Zhang H, Shi F, et al.: Epidemiology and outcome analysis of scalds in children caused by “guo lian kang”: An 11-year review in a burn center in China. Burns. 2015 Mar 1 [cited 2021 Jun 19]; 41(2): 289–96. PubMed Abstract | Publisher Full Text Reference Source\n\nRimmer RB, Weigand S, Foster KN, et al.: Scald burns in young children- A review of arizona burn center pediatric patients and a proposal for prevention in the hispanic community. J Burn Care Res. 2008 Jul [cited 2021 Jun 19]; 29(4): 595–605. PubMed Abstract | Publisher Full Text Reference Source\n\nWang S, Li D, Shen C, et al.: Epidemiology of burns in pediatric patients of Beijing City. BMC Pediatr. 2016 Oct 18 [cited 2021 Jun 19]; 16(1): 166. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nPathak BD, Nakarmi KK, Shrestha D, et al.: Comparison of Accidental Pediatric Scald Burns in a Tertiary Care Center: Hot Cauldron Burns versus Accidental Spill Burns.sav. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "97945",
"date": "03 Nov 2021",
"name": "Saidur Rahman Mashreky",
"expertise": [
"Reviewer Expertise Injury Prevention including burns",
"Non Communicable disease including mental 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\nThank you for conducting an exciting study in the field of burn prevention.\nThe study's title is 'Comparison of accidental pediatric scald burns in a tertiary care center: hot cauldron burns versus accidental spill burns'. The study aimed to compare accidental spill and immersion (hot cauldron) scald burns in a tertiary care center and assess morbidity and mortality caused by them.\nThe objective of the study is less clear. However, in this study, the authors tried to determine the type of scald burn that is more prevalent and attempted to explore the association between the type of scald burn and the severity of morbidity and mortality. However, to answer this kind of research question, authors need to select an analytical study design.\n\nThe conclusion section of the article was not much aligned with your study title and objective.\nIn my understanding, it is better to redesign the study to see the distribution of scald burn and its consequence.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7626",
"date": "10 Jan 2022",
"name": "Bishnu Pathak",
"role": "Author Response",
"response": "Dear Sir, Thank you very much for reviewing our article and for providing healthy, constructive, and relevant comments. We owe you a great debt of gratitude for the same. We have tried to make the necessary corrections as suggested by you in the new version. There are a few things that we would like to put forward. 1. You have commented on the design of the study. Our study is an analytical cross-sectional study. We have done comparisons at two different levels. Firstly, between the types of burns (hot cauldron burns and accidental spill burns). Secondly, a comparison is done between survivors and non-survivors, though this is not mentioned in the title of the article. It is because our primary objective was to analyze the types of scald burns in children. But, during analysis, we found many factors interestingly affecting the mortality, due to which we did a second comparison as well. This could be helpful to the scientific literature that is lacking these sorts of findings. 2. We have written the conclusion as suggested by you, such that it sounds being aligned with the tile of the study. 3. We have also tried to write objectives more clear than before. We humbly request you to look upon these changes. Thank you Regards Bishnu Deep Pathak"
}
]
},
{
"id": "100987",
"date": "21 Dec 2021",
"name": "Roshan Acharya",
"expertise": [
"Reviewer Expertise Clinical",
"Critical Care",
"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\nThe authors have tried to compare the prevalence and outcome of hot cauldron burns versus accidental spill burns in a tertiary care hospital.\n\nThe authors have also explored various factors that are associated with mortality in burn patients in the hospital.\n\nThe statistical methods are sound and the results are well presented.\n\nThe authors have well discussed the existing relevant literature. However, as the authors have rightly pointed out, the number of the patients included in the study seems to be low for the number of cases, but it is understandable being a single center study taking pediatric burn patients. Secondly, the prevalence of different types of burn cases may not be relevant in other settings.\n\nOverall, the study has been well conducted and the manuscript has been well written according to the context.\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/10-1086
|
https://f1000research.com/articles/11-18/v1
|
07 Jan 22
|
{
"type": "Software Tool Article",
"title": "skater: an R package for SNP-based kinship analysis, testing, and evaluation",
"authors": [
"Stephen D. Turner",
"V.P. Nagraj",
"Matthew Scholz",
"Shakeel Jessa",
"Carlos Acevedo",
"Jianye Ge",
"August E. Woerner",
"Bruce Budowle",
"V.P. Nagraj",
"Matthew Scholz",
"Shakeel Jessa",
"Carlos Acevedo",
"Jianye Ge",
"August E. Woerner",
"Bruce Budowle"
],
"abstract": "Motivation: SNP-based kinship analysis with genome-wide relationship estimation and IBD segment analysis methods produces results that often require further downstream process- ing and manipulation. A dedicated software package that consistently and intuitively imple- ments this analysis functionality is needed. Results: Here we present the skater R package for SNP-based kinship analysis, testing, and evaluation with R. The skater package contains a suite of well-documented tools for importing, parsing, and analyzing pedigree data, performing relationship degree inference, benchmarking relationship degree classification, and summarizing IBD segment data. Availability: The skater package is implemented as an R package and is released under the MIT license at https://github.com/signaturescience/skater. Documentation is available at https://signaturescience.github.io/skater.",
"keywords": [
"bioinformatics",
"kinship",
"R",
"genealogy",
"SNPs",
"single nucleotide polymorphisms",
"relatedness"
],
"content": "Introduction\n\nInferring familial relationships between individuals using genetic data is a common practice in population genetics, medical genetics, and forensics. There are multiple approaches to estimating relatedness between samples, including genome-wide measures, such as those implemented in Plink1 or KING,2 and methods that rely on identity by descent (IBD) segment detection, such as GERMLINE,3 hap-IBD,4 and IBIS.5 Recent efforts focusing on benchmarking these methods6 have been aided by tools for simulating pedigrees and genome-wide SNP data.7 Analyzing results from genome-wide SNP-based kinship analysis or comparing analyses to simulated data for benchmarking have to this point required writing one-off analysis functions or utility scripts that are seldom distributed with robust documentation, test suites, or narrative examples of usage. There is a need in the field for a well-documented software package with a consistent design and API that contains functions to assist with downstream manipulation, benchmarking, and analysis of SNP-based kinship assessment methods. Here we present the skater package for SNP-based kinship analysis, testing, and evaluation with R.\n\n\nMethods\n\nThe skater package provides an intuitive collection of analysis and utility functions for SNP-based kinship analysis. Functions in the package include tools for importing, parsing, and analyzing pedigree data, performing relationship degree inference, benchmarking relationship degree classification, and summarizing IBD segment data, described in full in the Use Cases section below. The package adheres to “tidy” data analysis principles, and builds upon the tools released under the tidyverse R ecosystem.8\n\nThe skater package is hosted in the Comprehensive R Archive Network (CRAN) which is the main repository for R packages: http://CRAN.R-project.org/package=skater. Users can install skater in R by executing the following code:\n\nAlternatively, the development version of skater is available on GitHub at https://github.com/signaturescience/skater. The development version may contain new features which are not yet available in the version hosted on CRAN. This version can be installed using the install_github() function in the devtools package:\n\nWhen installing skater, other packages which skater depends on are automatically installed, including magritr, tibble, dplyr, tidyr, readr, purrr, kinship2, corrr, rlang, and others.\n\nMinimal system requirements for installing and using skater include R (version 3.0.0 or higher) and several tidyverse packages8 that many R users will already have installed. Use cases are demonstrated in detail below. In summary, the skater package has functions for:\n\n• Reading in various output files produced by commonly used tools in SNP-based kinship analysis\n\n• Pedigree parsing, manpulation, and analysis\n\n• Relationship degree inference\n\n• Benchmarking and assessing relationship classification accuracy\n\n• IBD segment analysis post-processing\n\nA comprehensive reference for all the functions in the skater package is available at https://signaturescience.github.io/skater/.\n\n\nUse cases\n\nThe skater package provides a collection of analysis and utility functions for SNP-based kinship analysis, testing, and evaluation as an R package. Functions in the package include tools for working with pedigree data, performing relationship degree inference, assessing classification accuracy, and summarizing IBD segment data.\n\nPedigrees define familial relationships in a hierarchical structure. One of the common formats used by PLINK1 and other genetic analysis tools is the.fam file. A.fam file is a tabular format with one row per individual and columns for unique IDs of the mother, father, and the family unit. The package includes read_fam() to read files in this format:\n\nFamily structures imported from.fam formated files can then be translated to the pedigree structure used by the kinship2 package.9 The “fam” format may include multiple families, and the fam2ped() function will collapse them all into a tibble with one row per family:\n\nIn the example above, the resulting tibble is nested by family ID. The data column contains the individual family information, while the ped column contains the pedigree object for that family. Using standard tidyverse operations, the resulting tibble can be unnested for any particular family:\n\nA single pedigree can also be inspected or visualized (standard base R plot arguments such as mar or cex can be used to adjust aesthetics):\n\nThe plot_pedigree() function from skater will iterate over a list of pedigree objects, writing a multi-page PDF, with each page containing a pedigree from family:\n\nThe ped2kinpair() function takes a pedigree object and produces a pairwise list of relationships between all individuals in the data with the expected kinship coefficients for each pair.\n\nThe function can be run on a single family:\n\nThis function can also be mapped over all families in the pedigree:\n\nNote that this maps ped2kinpair() over all ped objects in the input tibble, and that relationships are not shown for between-family relationships.\n\nThe skater package includes functions to translate kinship coefficients to relationship degrees. The kinship coefficients could come from ped2kinpair() or other kinship estimation software.\n\nThe dibble() function creates a degree inference tibble, with degrees up to the specified max_degree (default=3), expected kinship coefficient, and lower (l) and upper (u) inference ranges as defined in Manichaikul et al.2 Degree 0 corresponds to self/identity/monozygotic twins, with an expected kinship coefficient of 0.5, with inference range >=0.354. Anything beyond the maximum degree resolution is considered unrelated (degree NA). Note also that while the theoretical upper boundary for the kinship coefficient is 0.5, the inference range for 0-degree (same person or identical twins) extends to 1 to allow for floating point arithmetic and stochastic effects resulting in kinship coefficients above 0.5.\n\nThe degree inference max_degree default is 3. Change this argument to allow more granular degree inference ranges:\n\nNote that the distance between relationship degrees becomes smaller as the relationship degree becomes more distant. The dibble() function will emit a warning with max_degree >=10, and will stop with an error at >=12.\n\nThe kin2degree() function infers the relationship degree given a kinship coefficient and a max_degree up to which anything more distant is treated as unrelated. Example first degree relative:\n\nExample 4th degree relative, but using the default max_degree resolution of 3:\n\nExample 4th degree relative, but increasing the degree resolution:\n\nThe kin2degree() function is vectorized over values of k, so it can be used inside of a mutate on a tibble of kinship coefficients:\n\nOnce estimated kinship is converted to degree, it may be of interest to compare the inferred degree to truth. When aggregated over many relationships and inferences, this approach can help benchmark performance of a particular kinship analysis method.\n\nThe skater package adapts a confusion_matrix() function from Clark10 to provide standard contingency table metrics (e.g. sensitivity, specificity, PPV, precision, recall, F1, etc.) with a new reciprocal RMSE (R-RMSE) metric. The confusion_matrix() function on its own outputs a list with four objects:\n\n1. A tibble with calculated accuracy, lower and upper bounds, the guessing rate and p-value of the accuracy vs. the guessing rate.\n\n2. A tibble with contingency table statistics calculated for each class. Details on the statistics calculated for each class can be reviewed on the help page for ?confusion_matrix.\n\n3. A matrix with the contingency table object itself.\n\n4. A vector with the reciprocal RMSE (R-RMSE). The R-RMSE represents an alternative to classification accuracy when benchmarking relationship degree estimation and is calculated using the formula in (1). Taking the reciprocal of the target and predicted degree results in larger penalties for more egregious misclassifications (e.g., classifying a first-degree relative pair as second degree) than misclassifications at more distant relationships (e.g., misclassifying a fourth-degree relative pair as fifth-degree). The +0.5 adjustment prevents division-by-zero when a 0th-degree (identical) relative pair is introduced.\n\nTo illustrate the usage, this example will start with the kinpairs data from above and randomly flip ~20% of the true relationship degrees:\n\nNext, running the confusion_matrix() function will return all four objects noted above:\n\nStandard tidyverse functions such as purrr::pluck() can be used to isolate just the contingency table:\n\nThe confusion_matrix() function includes an argument to output in a tidy (longer=TRUE) format, and the example below illustrates how to spread contingency table statistics by class:\n\nTools such as hap-IBD,4 and IBIS5 detect shared IBD segments between individuals. The skater package includes functionality to take those IBD segments, compute shared genomic centimorgan (cM) length, and converts that shared cM to a kinship coefficient. In addition to inferred segments, these functions can estimate “truth” kinship from simulated IBD segments.7 The read_ibd() function reads pairwise IBD segments from IBD inference tools and from simulated IBD segments. The read_map() function reads in genetic map in a standard format which is required to translate the total centimorgans shared IBD to a kinship coefficient using the ibd2kin() function. See ?read_ibd and ?read_map for additional details on expected format.\n\nThe read_ibd() function reads in the pairwise IBD segment format. Input to this function can either be inferred IBD segments from hap-IBD (source=\"hapibd\") or simulated segments (source=\"pedsim\"). The first example below uses data in the hap-ibd output format:\n\nIn order to translate the shared genomic cM length to a kinship coefficient, a genetic map must first be read in with read_map(). Software for IBD segment inference and simulation requires a genetic map. The map loaded for kinship estimation should be the same one used for creating the shared IBD segment output. The example below uses a minimal genetic map that ships with skater:\n\nThe ibd2kin() function takes the segments and map file and outputs a tibble with one row per pair of individuals and columns for individual 1 ID, individual 2 ID, and the kinship coefficient for the pair:\n\n\nSummary\n\nThe skater R package provides a robust software package for data import, manipulation, and analysis tasks typically encountered when working with SNP-based kinship analysis tools. All package functions are internally documented with examples, and the package contains a vignette demonstrating usage, inputs, outputs, and interpretation of all key functions. The package contains internal tests that are automatically run with continuous integration via GitHub Actions whenever the package code is updated. The skater package is permissively licensed (MIT) and is easily extensible to accommodate outputs from new genome-wide relatedness and IBD segment methods as they become available.\n\n\n\n1. Software available from: http://CRAN.R-project.org/package=skater.\n\n2. Source code available from: https://github.com/signaturescience/skater.\n\n3. Archived source code at time of publication: https://doi.org/10.5281/zenodo.5761996.11\n\n4. Software license: MIT License.\n\nSDT, VPN, and MBS developed the R package.\n\nAll authors contributed to method development.\n\nSDT wrote the first draft of the manuscript.\n\nAll authors assisted with manuscript revision.\n\nAll authors read and approved the final manuscript.\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThis work was supported in part by award 2019-DU-BX-0046 (Dense DNA Data for Enhanced Missing Persons Identification) to B.B., awarded by the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice and by internal funds from the Center for Human Identification. The opinions, findings, and conclusions or recommendations expressed are those of the authors and do not necessarily reflect those of the U.S. Department of Justice.",
"appendix": "References\n\nPurcell S, Neale B, Todd-Brown K, et al.: PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. Am. J. Hum. Genet. September 2007; 81(3): 559–575. PubMed Abstract | Publisher Full Text\n\nManichaikul A, Mychaleckyj JC, Rich SS, et al.: Robust relationship inference in genome-wide association studies. Bioinformatics (Oxford, England). November 2010; 26(22): 2867–2873. PubMed Abstract | Publisher Full Text\n\nGusev A, Lowe JK, Stoffel M, et al.: Whole population, genome-wide mapping of hidden relatedness. Genome Res. February 2009; 19(2): 318–326. PubMed Abstract | Publisher Full Text\n\nZhou Y, Browning SR, Browning BL: A Fast and Simple Method for Detecting Identity-by-Descent Segments in Large-Scale Data. Am. J. Hum. Genet. April 2020; 106(4): 426–437. PubMed Abstract | Publisher Full Text\n\nSeidman DN, Shenoy SA, Kim M, et al.: Rapid, Phase-free Detection of Long Identity-by-Descent Segments Enables Effective Relationship Classification. Am. J. Hum. Genet. April 2020; 106(4): 453–466. PubMed Abstract | Publisher Full Text\n\nRamstetter MD, Dyer TD, Lehman DM, et al.: Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives. Genetics. September 2017; 207(1): 75–82. PubMed Abstract | Publisher Full Text\n\nCaballero M, Seidman DN, Qiao Y, et al.: Crossover interference and sex-specific genetic maps shape identical by descent sharing in close relatives. PLoS Genet. December 2019; 15(12): e1007979. PubMed Abstract | Publisher Full Text\n\nWickham H, Averick M, Bryan J, et al.: Welcome to the tidyverse. J. Open Source Softw. 2019; 4(43): 1686. Publisher Full Text\n\nSinnwell JP, Therneau TM, Schaid DJ: The kinship2 R Package for Pedigree Data. Hum. Hered. 2014; 78(2): 91–93. PubMed Abstract | Publisher Full Text\n\nClark M: January 2021. Reference Source\n\nStephen T, Nagraj VP, Matthew S: signaturescience/skater: v0.1.0 (v0.1.0). Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "119026",
"date": "19 Jan 2022",
"name": "Wei-Min Chen",
"expertise": [
"Reviewer Expertise My area of research is statistical genetics",
"specifically developing methods and tools for relatedness inference."
],
"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 developed an R package to evaluate the performance of different relatedness inference tools. Both the R package and the manuscript are user-friendly and easy to follow. This tool should be timely and valuable to geneticists (or data analysts) who have a need to compare different relatedness inference tools and choose a tool that performs the best for their own genetic datasets. The manuscript is very well written.\nOne very minor comment is about the format requirement for the developed tool. Is the required format basically PLINK with expectations that some commonly used PLINK formats are still not allowed, or all PLINK format is acceptable? E.g.,\nHow about only one parent available, with Father ID 1234 and mother ID 0? This is allowed and considered as PLINK format. How does the proposed tool handle it, e.g., ask the user to reformat it?\n\nHow about both parents only with IDs available. E.g., Father ID is 1234 and mother ID is 5678, and none of them have appeared again in Individual IDs?\n\nAgain, the comment above is quite minor and may only require some clarification. The overall quality of this manuscript is great.\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": "119020",
"date": "26 Jan 2022",
"name": "Magnus Dehli Vigeland",
"expertise": [
"Reviewer Expertise Statistical genetics",
"pedigree analysis",
"R"
],
"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\nFor many researchers, myself included, R is the language-of-choice when it comes to downstream analysis and tidying-up the output of other programs. This inevitably leads to a disorganized body of ad hoc scripts for parsing, cleaning, and manipulating various result files. Arguably, the best solution to this problem is to collect related scripts into an R package, which can be properly documented, version-controlled, and potentially shared with others. The skater package presented in this paper is precisely such a package, aimed at the users of several popular software for relatedness estimation, including KING, PLINK, hap-IBD, and others. A specific goal of the package is to provide tools that work consistently across these programs.\nThe paper is written in clear language, well structured, and easy to follow. Parts of the paper resemble a user manual, including detailed code examples. I enjoyed playing around with the package, which is well organized and documented. In particular, I appreciate the thorough input checks and helpful error messages when things go wrong. The package may not offer a ton of novel methods yet, but I can certainly see myself using it the next time I run some of these relatedness programs.\nBelow are a few issues I have with the manuscript.\nIt would be helpful to clarify what sort of applications skater is intended for. The introduction mentions \"relationship inference in population genetics, medical genetics, and forensics\", but that seems overly broad. The focus is on simple measures like the kinship coefficient and relatedness degree (rather than detailed coefficients and actual genealogical relationships) suggesting large-scale applications rather than small-scale pedigree analysis as e.g. in forensic case work. Indeed, all the programs referenced in the paper are intended for large-scale population studies. Furthermore, it seems to be an underlying assumption that all individuals are noninbred (suggested e.g. by the statement \"the theoretical upper boundary for the kinship coefficient is 0.5\"), and also that they are human (by the hardcoded 3560 cM genome length). To be clear, I think these limitations and assumptions are perfectly fine, but it would be better to state (or discuss) them more clearly.\n\nA connection to \"SNP-based methods\" is mentioned repeatedly, but never really explained. Is there one? I note at least one of the cited programs (hap-IBD) is designed to work with sequencing data. Does it matter for skater how the kinship estimates were obtained?\n\nThe function `confusion_matrix()` produces an impressive array of summary stats when comparing inferred kinship degrees to true ones. This is great, but I wonder about the origin of this function. In my understanding, it is a modified version of a function from another package, confusionMatrix, written by Michael Clark (not an author of the paper). Several related functions appear to be copied verbatim into skater. All of this is clearly marked in the code, with Clark rightfully listed as author, and Clark's package does come with a permissive license (MIT), but I still find it a bit odd. Why not simply import it? That way, bug fixes and improvements in the original version would automatically propagate to skater, avoiding the confusion of multiple versions. If the problem is that confusionMatrix is not on CRAN, perhaps one could reach out to make this happen?\n\nIn the example illustrating `confusion_matrix()`, the authors construct a dataset by modifying a previous one, by \"randomly flipping ~20% of the true degrees\". The term \"flip\" sounds misplaced to me here, since the variable isn't dichotomous. Also, the procedure doesn't change 20%, only 0.2 * 4/5 = 16% on average, since the new values are generated from the complete set and stay unchanged with probability 1/5. Regardless of these minor issues, I must admit I found the example rather artificial. It would be much more interesting to see confusion_matrix() applied to a real dataset! That could also motivate some comments on how its output should be interpreted.\nFinally, I cannot resist offering a couple of suggestions for the skater package itself:\nThe `read_fam()` for reading .fam files is very strict, insisting on space-separated columns and disallowing any format deviations. I note that e.g. PLINK, and several other R packages that read pedigree files, allow variations like tab-separated columns and missing phenotype column; perhaps this could be useful in the skater package too.\n\nSeparating parent-offspring pairs from full sibs is a crucial step in many relatedness studies, and often possible by a simple analysis of the output of e.g. KING. Does skater offer such differentiation? If not, it might make a nice addition to the package in the future.\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": []
},
{
"id": "119025",
"date": "14 Feb 2022",
"name": "Amy L. Williams",
"expertise": [
"Reviewer Expertise Relatedness in large datasets."
],
"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 an R package that provides a suite of tools for performing kinship and IBD segment analysis. Key features include methods for reading and analyzing pedigree data, inferring relationships, benchmarking relationship degree classification, and IBD segment analyses. The use cases in this article and the R reference manual on CRAN together provide exemplary documentation for skater. Users unfamiliar with pedigree-style analyses and/or who desire a clean, well documented interface for performing these analyses can find a great deal of utility in this R package.\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": []
}
] | 1
|
https://f1000research.com/articles/11-18
|
https://f1000research.com/articles/11-16/v1
|
07 Jan 22
|
{
"type": "Systematic Review",
"title": "Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review",
"authors": [
"Kurosh Mojtabavi",
"Morteza Gholami",
"Zahra Ghodsi",
"Narges Mahmoodi",
"Sina Shool",
"Saeed Kargar-Soleimanabad",
"Niloufar Yazdanpanah",
"Alexander R. Vaccaro",
"Vafa Rahimi-Movaghar",
"Kurosh Mojtabavi",
"Morteza Gholami",
"Zahra Ghodsi",
"Narges Mahmoodi",
"Sina Shool",
"Saeed Kargar-Soleimanabad",
"Niloufar Yazdanpanah",
"Alexander R. Vaccaro"
],
"abstract": "Background: In many cases, central nervous system (CNS) injury is unchanging due to the absence of neuronal regeneration and repair capabilities. In recent years, regenerative medicine, and especially hydrogels, has reached a significant amount of attention for their promising results for the treatment of spinal cord injury (SCI) currently considered permanent. Hydrogels are categorized based on their foundation: synthetic, natural, and combination. The objective of this study was to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI. Methods: Articles were searched in PubMed, Scopus, Web of Science, and Embase. All studies from 1985 until January 2020 were included in the primary search. Eligible articles were included based on the following criteria: administering hydrogels (both natural and synthetic) for SCI treatment, solely focusing on spinal cord injury treatment, and published in a peer-reviewed journal. Data on axonal regeneration, revascularization, elasticity, drug delivery efficacy, and porosity were extracted. Results: A total of 24 articles were included for full-text review and data extraction. There was only one experimental study comparing collagen I (natural hydrogel) and polyethylene glycol (PEG) in an in vitro setting. The included study suggested the behavior of cells with PEG is more expectable in the injury site, which makes it a more reliable scaffold for neurites. Conclusions: There is limited research comparing and evaluating both types of natural and self-assembling peptides (SAPs) in the same animal or in vitro study, despite its importance. Although we assume that the remodeling of natural scaffolds may lead to a stable hydrogel, there was not a definitive conclusion that synthetic hydrogels are more beneficial than natural hydrogels in neuronal regeneration.",
"keywords": [
"Hydrogels",
"Collagen",
"Peptides",
"Spinal cord Injuries",
"Systematic review"
],
"content": "Introduction\n\nInjuries to the central nervous system (CNS) are challenging to rehabilitate. In the absence of neuronal regeneration and repair capabilities, the damage and resulting complications are permanent in many cases. There have not been any new treatments for spinal cord injury (SCI) in the past decade, and many studies in molecular medicine currently consider some spinal cord conditions as untreatable.1\n\nA permissive growth substrate is critical to promote regeneration at the injury site.2 Many types of research have been conducted to advance and evaluate different natural and synthetic hydrogel systems,3 such as polysaccharides,4,5 synthetic polymers,6 proteins,7 peptides,8 and its derivatives.9–11\n\nHydrogels are categorized as natural and synthetic structures with properties for extensive water absorption and resistance to dissolution.12 We consider a perfect hydrogel to provide the following features: 1) high absorption capacity, 2) low soluble content and residue, 3) suitable biodegradability based on tissue type and the absence of toxic species formation, 4) local and sustained drug-release, 5) immunologically inert, and 6) substantial cost-benefit.12–14\n\nBoth natural and synthetic hydrogels have different characteristics, and some of them are compatible with the features listed above.\n\nSelf-assembling peptides (SAPs) can spontaneously self-assemble in the aqueous solution to form highly organized structures, such as hydrogels. Due to their great water-holding capacity, outstanding biocompatibility,15–17 and similarities to the native extracellular matrix (ECM),18 these hydrogels have gained tremendous recognition in recent years. The advantages of these artificial hydrogels are their transmutative characteristics, such as porosity, elasticity, and drug delivery pace.19\n\nFor a previous project, we asked several distinguished companies in China, Denmark, Canada, and more to design and produce high concentration hydrogels. However, they could not produce SAPs with a desirable concentration percentage for cell culture purposes, which in some cases can be considered as a challenge of providing this type of scaffolds.\n\nOn the other hand, many studies have applied natural hydrogels like collagen-based hydrogel designed based on the Nature Protocols20 for drug delivery in spinal cord injuries in animals, and the results have been somewhat promising. Due to their soft tissue-like formation characteristics, agarose, alginate, and collagen hydrogels have been acknowledged as likely scaffolds in the CNS and the peripheral nervous system (PNS).21–23 Therefore, we performed this review to determine how these two very different, yet very promising, scaffolds would perform in similar conditions.\n\n\nMethod\n\nThe Ethics Committee of Tehran University of Medical Sciences, approved the study with reference number 99-1-101-388. This systematic review has been conducted according to the PRISMA 2020 Checklist.24,25\n\nIn the review, articles had to meet the following inclusion criteria: 1) administering hydrogels (both natural and synthetic) for SCI treatment, 2) specifically focused on spinal cord injury, and 3) original articles published in a peer-reviewed journal. Exclusion criteria included: 1) studies on injuries other than SCI, 2) studies focusing on only tissue-engineered self-assembling peptides, 3) studies focused only on natural hydrogels.\n\nThere was no limitation of language for included studies.\n\nWe performed this systematic review to evaluate axonal regeneration, revascularization, porosity, elasticity, and drug delivery efficacy of natural and synthetic hydrogels. Our search strategy in different databases utilized Medical Subject Headings (MeSH, from PubMed), Excerpta Medica Tree (Emtree, from Embase), keywords of related articles and reviews, and experts' opinions. A systematic search of the literature was performed on PubMed, Scopus, Web of Science, and Embase for published articles from 1985 until January 2020. The detailed search syntax is presented in the Extended data.24 We also manually checked the references of primarily included studies and relevant reviews to identify additional relevant articles. After removing duplicate articles, the remaining articles were transferred to an EndNote file (version X9, Thomson Reuters, USA).\n\nAfter eliminating duplicates, the records were divided into two groups. Each group was reviewed by two independent reviewers (in two teams) based on the keywords, and 24 papers were selected eligible for full-text review. The resulting records were then divided again and each full text was reviewed by two independent reviewers (in two teams) for data extraction. Differences of opinion between two reviewers of each team was solved by consultation with the corresponding author.\n\nWe designed a data collection sheet, and the items below were collected to compare natural and self-assembling hydrogels:\n\n• Axonal regeneration: The axon (proximal fragment) regrowth from the injury site toward its target following the original pathway.\n\n• Revascularization: restoration of the flow of blood to a previously ischemic tissue after a traumatic injury.\n\n• Porosity: a fraction of the volume of voids over the total volume. Hydrogel porosity is critical for local angiogenesis and has a substantial effect on the mechanical properties\n\n• Elasticity: the ability of a hydrogel to resume its standard shape after implantation.\n\n• Invasion/Elongation of astrocytes, fibroblasts, endothelial or Schwann cells\n\n• Efficacy of drug delivery\n\n\nResults\n\nOut of a total number of 2742 identified articles, 2718 records were excluded based on title and abstract screening, and the full text of the remaining 24 records were investigated by the same four reviewers as two review groups. In total, 23 were excluded at this stage and only one record was selected for full-text review (Figure 1). Of the 23 articles excluded, 18 were because they did not evaluate a natural hydrogel in their study,26–43 and five because they had not administrated a SAP in the study.44–48\n\nAccording to the single record included (Table 1), axonal regeneration of the administrated scaffolds was reported individually based on the type and the combination of scaffolds.\n\nIn this study, with the addition of fibronectin (FN) at various concentrations to PEG gels, and collagen I in various concentrations and stiffness, cell behavior and axonal regeneration were investigated in an in vitro environment shown in Table 2. The article found that adding FN to collagen has a biphasic response due to specific interactions in collagen and the growing neurites, contrary to PEG, which has a more expectable behavior regarding the FN addition within the graft.\n\nPEG gels were examined at 3%, 4%, and 5% concentration with 0, 1, 10, 100 μg/ml FN added; 3% PEG+ 100 μg/ml FN presented the most significant neurite length growth by 145 μm. It is also worth remarking that adding any concentrations of FN to PEG gels had a positive effect on axonal regeneration than PEG gels with no FN added.\n\nCollagen I was examined at 0.4-2 mg/ml concentrations with 0, 1, 10, 100 μg/ml FN added; As mentioned above, the addition of FN had a biphasic response in collagen, with reducing neurite growth length in lower concentrations (0.4-0.6 mg/ml) compared to collagens with no FN, while increasing neurites length in mid and high collagen concentrations (1.0-2.0 mg/ml).\n\nWhile the addition of FN impacted the overall growth within the different gels, there were no differences noted in viability with increasing FN concentrations. No differences were found between PEG gel concentrations. Moreover, cells within collagen gels had higher viability overall.\n\n\nDiscussion\n\nWe believe biomaterials and natural hydrogels are expected to not dissolve quickly and remain for a long time when injected into the injured spinal cord whilst directly delivering drugs into it, and render a sufficient environment for axonal regeneration and revascularization of the damaged tissues. Also, these scaffolds help with the need for a physical matrix to which neurons and endogenous repairing cells can adhere.49\n\nIn this regard, designing a hydrogel must meet some fundamental principles, such as biocompatibility, so it does not trigger an immune response from the host49; specifically designed mechanical and physicochemical characteristics allow both spinal cord stabilization and cell adherence and growth.26\n\nThe biodegradability of these materials must be considered, and the biomaterial degrades as new tissue grows, mimicking the natural mechanisms of breakdown and synthesis of ECM in the natural tissue.50–54\n\nIn a previous study, Merchand et al. used collagen as scaffolds to fill the gap transected in the spinal cord of Sprague-Dawley rats, and extended the stability of collagen (2-3 months) by adding a cross-linking agent to the gel which helped axonal regrowth over a six months' timeline.56\n\nThe biocompatibility characteristics of natural hydrogels allow for cell adhesion and migration.57 Moreover, not only can natural hydrogels be used to bridge the gap in the lesion site for cell regeneration, but they are also considered for sustained drug delivery.58\n\nHowever, synthetic hydrogels, such as poly (hydroxyethyl methacrylate) (PHEMA) based hydrogels, are favorites for the treatment of SCI and drug delivery to the lesion site due to their ability to be mass produced and their ability to have their properties modified.59\n\nOur study indeed had some limitations. Regenerative studies for SCI primarily focus on different characteristics of one specific type of hydrogel and, comparing different features of these types of hydrogels were completely overlooked, or if these two types of hydrogels are used together in a study, it is in the form of a new combinatorial hydrogel scaffold.\n\nThere are no definitive findings regarding synthetic hydrogels' advantage over natural hydrogels in SCI treatment in animals or humans. Still, there might be some inadequate shreds of evidence to report that one of these types has an advantage over the other. However, more studies with the specific objective to compare synthetic and natural hydrogels is necessary to find their advantages and disadvantages in a mutual condition. Until then, both synthetic and natural scaffolds are in the race for the ultimate scaffolds.\n\nThis study sheds light on a notable absence of evaluation following our objectives and intentions performing this review.\n\n\nConclusion\n\nWe assume that remodeling natural scaffolds may lead to sensible axonal regeneration, progress such as reducing the scar tissue, and a stable graft at the injury site; however, there was not a definite evidence regarding the benefits of neuronal regeneration in synthetic hydrogels compared to natural hydrogels.\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: Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review. https://doi.org/10.5281/zenodo.5759312.25\n\nThis project contains the following extended data:\n\n- search strategy.docx\n\nZenodo: PRISMA checklist for ‘Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review’. https://doi.org/10.5281/zenodo.5759312.25\n\nData are available under the terms of the Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nGrant information\n\nThis work was supported by Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences. The grant number is 99-1-101-47039.",
"appendix": "References\n\nGazdic M, et al.: Stem Cells Therapy for Spinal Cord Injury. Int. J. Mol. Sci. 30 Mar. 2018; 19(4): 1039. PubMed Abstract | Publisher Full Text\n\nJain A, et al.: In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury. Biomaterials. 2006; 27(3): 497–504. Publisher Full Text\n\nHuang R, et al.: Self-assembling peptide–polysaccharide hybrid hydrogel as a potential carrier for drug delivery. Soft Matter. 2011; 7(13): 6222–6230. Publisher Full Text\n\nTan H, et al.: Injectable in situ forming biodegradable chitosan–hyaluronic acid-based hydrogels for cartilage tissue engineering. Biomaterials. 2009; 30(13): 2499–2506. PubMed Abstract | Publisher Full Text\n\nJin R, Teixeira LSM, Dijkstra PJ, et al.: Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials. 2009; 30: 2544–2551. 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Publisher Full Text\n\nBhattacharya S, Ghanashyam Acharya SN: Impressive Gelation in Organic Solvents by Synthetic, Low Molecular Mass, Self-Organizing Urethane Amides of l-Phenylalanine. Chem. Mater. 1999; 11(11): 3121–3132. Publisher Full Text\n\nAhmed EM: Hydrogel: Preparation, characterization, and applications: A review. J. Adv. Res. 2015; 6(2): 105–121. Publisher Full Text\n\nBaumann MD, et al.: Intrathecal delivery of a polymeric nanocomposite hydrogel after spinal cord injury. Biomaterials. 2010; 31(30): 7631–7639. Publisher Full Text\n\nHejčl A, et al.: Biocompatible hydrogels in spinal cord injury repair. Physiol. Res. 2008; 57(3): S121–S132. Publisher Full Text\n\nGuiseppi-Elie A: Electroconductive hydrogels: synthesis, characterization and biomedical applications. Biomaterials. 2010; 31(10): 2701–2716. PubMed Abstract | Publisher Full Text\n\nHoffman AS: Hydrogels for biomedical applications. Adv. Drug Deliv. Rev. 2002; 54(1): 3–12. 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PubMed Abstract | Publisher Full Text\n\nHouweling DA, et al.: Collagen containing neurotrophin-3 (NT-3) attracts regrowing injured corticospinal axons in the adult rat spinal cord and promotes partial functional recovery. Exp. Neurol. 1998; 153(1): 49–59. PubMed Abstract | Publisher Full Text\n\nLabrador RO, et al.: Influence of collagen and laminin gels concentration on nerve regeneration after resection and tube repair. Exp. Neurol. 1998; 149(1): 243–252. PubMed Abstract | Publisher Full Text\n\nMoher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6: e1000097. PubMed Abstract | Publisher Full Text\n\nKurosh M: Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review [Data set]. Zenodo. 2021. Publisher Full Text\n\nNomura H, et al.: Complete spinal cord transection treated by implantation of a reinforced synthetic hydrogel channel results in syringomyelia and caudal migration of the rostral stump. Neurosurgery. 2006; 59(1): 183–192; discussion 183-92. PubMed Abstract | Publisher Full Text\n\nTsai EC, et al.: Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006; 27(3): 519–533. PubMed Abstract | Publisher Full Text\n\nWang Q, et al.: Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair. Theranostics. 8(16): 4429–4446. 7 Aug. PubMed Abstract | Publisher Full Text\n\nWoerly S, et al.: Heterogeneous PHPMA hydrogels for tissue repair and axonal regeneration in the injured spinal cord. J. Biomater. Sci. Polym. Ed. 1998; 9(7): 681–711. PubMed Abstract | Publisher Full Text\n\nWoerly S, et al.: Spinal cord repair with PHPMA hydrogel containing RGD peptides (NeuroGel). Biomaterials. 2001; 22(10): 1095–1111. PubMed Abstract | Publisher Full Text\n\nBaumann MD, et al.: Intrathecal delivery of a polymeric nanocomposite hydrogel after spinal cord injury. Biomaterials. 2010; 31(30): 7631–7639. PubMed Abstract | Publisher Full Text\n\nChen BK, et al.: Comparison of polymer scaffolds in rat spinal cord: a step toward quantitative assessment of combinatorial approaches to spinal cord repair. Biomaterials. 2011; 32(32): 8077–8086. PubMed Abstract | Publisher Full Text\n\nCigognini D, et al.: Evaluation of mechanical properties and therapeutic effect of injectable self-assembling hydrogels for spinal cord injury. J. Biomed. Nanotechnol. 2014; 10(2): 309–323. PubMed Abstract | Publisher Full Text\n\nConova L, et al.: A pilot study of poly(N-isopropylacrylamide)-g-polyethylene glycol and poly(N-isopropylacrylamide)-g-methylcellulose branched copolymers as injectable scaffolds for local delivery of neurotrophins and cellular transplants into the injured spinal cord. J. Neurosurg. Spine. 2011; 15(6): 594–604. PubMed Abstract | Publisher Full Text\n\nHejčl A, Růžička J, Kekulová K, et al.: Modified Methacrylate Hydrogels Improve Tissue Repair after Spinal Cord Injury. Int. J. Mol. Sci. 2018; 19(9): 2481. PubMed Abstract | Publisher Full Text\n\nKang CE, et al.: Poly (ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system. J. Control. Release. 2010; 144(1): 25–31. PubMed Abstract | Publisher Full Text\n\nMadigan NN, et al.: Comparison of cellular architecture, axonal growth, and blood vessel formation through cell-loaded polymer scaffolds in the transected rat spinal cord. Tissue Eng. A. 2014; 20(21-22): 2985–2997. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKubinová Š, et al.: SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. J. Tissue Eng. Regen. Med. 2015; 9(11): 1298–1309. PubMed Abstract | Publisher Full Text\n\nLee J, et al.: Formulation of thrombin-inhibiting hydrogels via self-assembly of ionic peptides with peptide-modified polymers. Soft Matter. 2020; 16(15): 3762–3768. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSiddiqui AM, et al.: Defining Spatial Relationships Between Spinal Cord Axons and Blood Vessels in Hydrogel Scaffolds. Tissue Eng. Part A. 2021; 27(11-12): 648–664. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKubinova S, Tukmachev D, Forostyak S, et al.: Comparison of synthetic versus biologic hydrogel scaffolds in spinal cord injury treatment. J. Tissue Eng. Regen. Med. 2014; 8: 43–43.\n\nAustin JW, et al.: The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis. Biomaterials. 2012; 33(18): 4555–4564. PubMed Abstract | Publisher Full Text\n\nAndo K, et al.: Self-assembling Peptide Reduces Glial Scarring, Attenuates Posttraumatic Inflammation, and Promotes Neurite Outgrowth of Spinal Motor Neurons. Spine. 2016; 41(20): E1201–E1207. PubMed Abstract | Publisher Full Text\n\nEstrada V, et al.: Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol. Dis. 2014; 67: 165–179. PubMed Abstract | Publisher Full Text\n\nMarchand R, Woerly S: Transected spinal cords grafted with in situ self-assembled collagen matrices. Neuroscience. 1990; 36(1): 45–60. PubMed Abstract | Publisher Full Text\n\nShoichet MS, et al.: Intrathecal drug delivery strategy is safe and efficacious for localized delivery to the spinal cord. Prog. Brain Res. 2007; 161: 385–392. PubMed Abstract | Publisher Full Text\n\nWang Q, et al.: A Thermosensitive Heparin-Poloxamer Hydrogel Bridges aFGF to Treat Spinal Cord Injury. ACS Appl. Mater. Interfaces. 2017; 9(8): 6725–6745. PubMed Abstract | Publisher Full Text\n\nAbu-Rub MT, et al.: Nano-textured self-assembled aligned collagen hydrogels promote directional neurite guidance and overcome inhibition by myelin associated glycoprotein. Soft Matter. 2011; 7(6): 2770–2781. Publisher Full Text\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. Publisher Full Text\n\nRahimi-Movaghar V, et al.: Epidemiology of traumatic spinal cord injury in developing countries: a systematic review. Neuroepidemiology. 2013; 41(2): 65–85. PubMed Abstract | Publisher Full Text\n\nZhou W, Blewitt M, Hobgood A, et al.: Comparison of neurite growth in three dimensional natural and synthetic hydrogels. J. Biomater. Sci. Polym. Ed. 2013; 24(3): 301–314. PubMed Abstract | Publisher Full Text\n\nAssunção-Silva RC, et al.: Hydrogels and cell-based therapies in spinal cord injury regeneration. Stem Cells Int. 2015; 2015: 1–24. PubMed Abstract | Publisher Full Text\n\nXing H, Yin H, Sun C, et al.: Preparation of an acellular spinal cord scaffold to improve its biological properties. Mol. Med. Rep. 2019; 20(2): 1075–1084. PubMed Abstract | Publisher Full Text\n\nZhang N, Yan H, Wen X: Tissue-engineering approaches for axonal guidance. Brain Res. Rev. 2005; 49(1): 48–64. PubMed Abstract | Publisher Full Text\n\nLittle L, Healy KE, Schaffer D: Engineering biomaterials for synthetic neural stem cell microenvironments. Chem. Rev. 2008; 108(5): 1787–1796. PubMed Abstract | Publisher Full Text\n\nMarchand R, et al.: Evaluation of two cross-linked collagen gels implanted in the transected spinal cord. Brain Res. Bull. 1993; 30(3-4): 415–422. PubMed Abstract | Publisher Full Text\n\nMalafaya PB, Silva GA, Reis RL: Natural–origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv. Drug Deliv. Rev. 2007; 59(4-5): 207–233. Publisher Full Text\n\nHan Q, Sun W, Lin H, et al.: Linear Ordered Collagen Scaffolds Loaded with Collagen-Binding Brain-Derived Neurotrophic Factor Improve the Recovery of Spinal Cord Injury in Rats. Tissue Eng. Part A. Oct 2009; 15: 2927–2935. PubMed Abstract | Publisher Full Text\n\nShoichet MS: Polymer scaffolds for biomaterials applications. Macromolecules. 2010; 43(2): 581–591. Publisher Full Text"
}
|
[
{
"id": "321115",
"date": "11 Oct 2024",
"name": "Isabella Drew",
"expertise": [
"Reviewer Expertise Spinal Cord Injury repair (including hydrogels and SAPs)"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview of Mojtabavi et al – 2024\n\nStuart Hodgetts and Isabella Drew (PhD student)\n“SYSTEMATIC REVIEW Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review.”\n1) Review by Stuart Hodgetts The systematic review was first received in January 2022. Its original aims were “to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI”. After applying the inclusion and exclusion criteria, only one paper was considered for analysis. The result is therefore NOT a systematic review of these hydrogels in the treatment SCI, because the single paper was in fact only an in vitro study – and is not applicable to any in vivo comparison, since no animal models of SCI were used to test the scaffolds. This single paper effectively was a comparison of neurite outgrowth in varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels. This manuscript does very little than offer a very superficial precis of a single published study that by itself provides more information than the review offered here. It is therefore unclear what benefit or contribution this review makes to the field. There appears to be no attempt to include, or at the very least make mention of, any updates the total number of manuscripts that might be included since 2022. Therefore, its relevance nearly 3 years on comes under question. A recent systematic review El Husseiny et al 2024 [Ref - 1] appears to hold more relevance in terms of final comparisons (El-Husseiny et al 2024 - International Journal of Biological Macromolecules 260 (2024) 129323). Additionally, the senior author Rahimi-Movaghar also published in 2022 a systematic review and meta-analysis comparing the “Efficacy of hydrogels for repair of traumatic spinal cord” [Ref - 2] in Biomed Mater Res, which was an informative and timely publication. The Mojtabavi et al submission does little to promote the field forward, and would benefit from waiting until future studies that fit the selection criteria provide a more informative narrative.\nSpecific comments: Introduction “There have not been any new treatments for spinal cord injury (SCI) in the past decade, and many studies in molecular medicine currently consider some spinal cord conditions as untreatable”. Specify biological treatments? What about exoskeletons? Electrical spinal stimulation to bridge circuitry?\n“For a previous project, we asked several distinguished companies in China, Denmark, Canada, and more to design and produce high concentration hydrogels. However, they could not produce SAPs with a desirable concentration percentage for cell culture purposes, which in some cases can be considered as a challenge of providing this type of scaffolds.” Relevance? Why was cell culture the directive here?\nMethods I was unable to find a statement regarding updates since 2022. I would suggest the authors to add information or statement whether the criteria included searches for both pre clinal and clinical studies (i.e. https://clinicaltrials.gov/), or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.\nResults “In this study, with the addition of fibronectin (FN) at various concentrations to PEG gels, and collagen I in various concentrations and stiffness, cell behavior and axonal regeneration were investigated in an in vitro environment shown in Table 2.” How many studies compare these types of hydrogels simply in vitro....with no SCI requirements? How does the single paper in this review make the comparison relevant (inclusive) for SCI?\nDiscussion “We believe biomaterials and natural hydrogels are expected to not dissolve quickly and remain for a long time when injected into the injured spinal cord whilst directly delivering drugs into it, and render a sufficient environment for axonal”. Why? What is your evidence for this? “sufficient environment”…This seems a bit vague. Can the authors please clarify what do they wish to convey exactly here. Hydrogels alter the local environment but the vast majority of studies show little if any benefit to substantive regeneration and/or regrowth, and very few if any link them to specific functional improvements/outcomes.\n“Also, these scaffolds help with the need for a physical matrix to which neurons and endogenous repairing cells can adhere.” What are these “types of endogenous” cells - Kindly describe here.\n“The biodegradability of these materials must be considered, and the biomaterial degrades as new tissue grows, mimicking the natural mechanisms of breakdown and synthesis of ECM in the natural tissue” It was stated above that you believe they should “remain for a long time” - what is the optimum time for this (e.g. rodent vs human SCI...? acute vs chronic?)\n“Still, there might be some inadequate shreds of evidence to report that one of these types has an advantage over the other.” The highlighted term again seems a bit vague. Can the authors please clarify specifically what do they mean exactly here.\nIn summary, this systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Whether this warrants indexing as a peer reviewed manuscript is questionable. Please also see highlighted pdf document with highlighted concerns/changes by clicking on this link -\nhttps://f1000research.s3.amazonaws.com/linked/682333.Mojtabavi_et_al_2024_Comparing_natural_hydrogels_to_self_assembling_peptides_in_SCI_treatment_a_systematic_review_highlighted_suggestions.pdf\n\nRecommendation: Not approved\n2) Supplementary Review (invited) by PhD student Isabella Drew:\nNot approved (Maybe approved with reservations)\nThe systematic review aims to highlight the lack of studies comparing natural and synthetic hydrogel material for spinal cord injuries. Through their inclusion and exclusion criteria, only one paper was approved for analysis, which explored how varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels influenced neurite outgrowth. While it is important to address the lack of studies on this topic, I believe it is difficult to answer their research question from one article, and this manuscript may benefit from the following suggestions.\nMinor improvements\nIt is important that every sentence is referenced, and to ensure that each source at the end is included in the text, as reference 55 is not cited. To improve the flow of the review, I recommend the following:\nEnsure that you are consistent with your acronyms as you interchange between “spinal cord injuries” and “SCI” The way some sentences are written interrupt with the flow and readability of the review Some paragraphs are a sentence in length, and could be joined to the previous or subsequent paragraph\n\nMethods The inclusion and exclusion criteria may benefit from including more detail, such as whether the authors searched for both pre clinal and clinical studies, or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.\nMajor improvements\nSince only one paper was included in the systematic analysis, the following suggests may aid in strengthening the overall message.\nIntroduction While the authors explain that a permissive growth substrate is critical for regeneration at the injury site, and state the beneficial characteristics of both natural and synthetic hydrogels, an elaboration on this would provide sufficient context for the review. Specifically, instead of stating they “have gained tremendous recognition”, explain why this is the case and specific outcomes in relation to your data collection criteria i.e. axonal regeneration, revascularisation, invasion/elongation of astrocytes. I believe this is pertinent to strengthen your argument that more comparative studies need to be conducted to progress this therapy, if the audience understands their therapeutic potential that has been supported by primary articles. If the authors are limited by word count, then removing the second last paragraph could address this concern.\nResults The authors only address one of 6 data items stated in their methods: axonal regeneration. If the paper approved for analysis only contained information on a 6th of the data collection criteria, then it raises questions as to whether the methods (search and analysis criteria) need alteration. Additionally, this section seems a bit vague and would benefit from more elaboration such as “specific interactions in collagen” and “more expectable behaviour” in the third paragraph.\nDiscussion The synthesis of the included article reads more like a summary. The fact that only one paper has conducted a comparative analysis can be utilised to strengthen the argument if the authors refrain from utilising the current passive tone. There needs to be more analysis on the included paper.\nIn conclusion, the systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Although, since only one article was included in the results section, if the authors haven't provide a more in-depth analysis, it may be best written as a narrative review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? 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\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-16
|
https://f1000research.com/articles/11-14/v1
|
07 Jan 22
|
{
"type": "Research Article",
"title": "Estimation and human health risk assessment of organochlorine and organophosphate pesticide residues in raw milk collected in Kenya",
"authors": [
"Sheridan Wanjiku Philip",
"Vincent Madadi Odongo",
"Shem Oyoo Wandiga",
"Duke Gekonge Omayio",
"Mitchel Otieno Okumu",
"Vincent Madadi Odongo",
"Shem Oyoo Wandiga",
"Duke Gekonge Omayio",
"Mitchel Otieno Okumu"
],
"abstract": "Background: This study determined the levels of organochlorine (OCPs) and organophosphate (OPPs) pesticide residues in cow milk from Kiambu and camel milk from Isiolo and Laikipia. The human dietary intake and the potential consumer health risks were also evaluated. Methods: In total, 90 cow and 82 camel milk samples were collected and analyzed using gas chromatography tandem mass spectroscopy to determine the levels of OCPs and OPPs. The levels were compared to the maximum residue limits (MRLs) established by the Codex Alimentarius (CA), EU Pesticides Database (EUPD), and the United States Department of Agriculture. The estimated daily intake and chronic hazard quotient (cHQ) of the milk were also calculated. Results: Cow milk from Kiambu was contaminated with 11/18 of the evaluated OCPs and 13/14 of the evaluated OPPs while camel milk from Isiolo was contaminated with 9/18 of the evaluated OCPs and 9/14 of the evaluated OPPs. Camel milk from Laikipia was contaminated with 11/18 of the evaluated OCPs and 11/14 of the evaluated OPPs. The mean heptachlor value in camel milk from Isiolo was above the EUPD MRLs. The mean value of heptachlor in Camel milk from Laikipia was above the CA and EUPD MRLs. The cHQs for Disulfoton, Fenamiphos, and Methacrifos in Cow milk were above 1 for adults and children. The cHQs for Fenchlorphous and Profenofos in Camel milk were above 1 for adults and children. The cHQs for α-endosulphan, β-endosulphan, dieldrin, and heptachlor in cow milk was above 1 for adults and children while the cHQs for heptachlor in camel milk was above 1 for adults and children. Conclusions: The potential health risks from chronic dietary intake of cow and camel milk in Kenya cannot be excluded. The routine monitoring of organophosphate and organochlorine pesticide levels in milk is recommended to minimize risks to human health.",
"keywords": [
"Pesticide residue limits",
"milk",
"milk quality",
"organophosphates",
"organochlorines",
"public health",
"public safety"
],
"content": "Introduction\n\nRapid urbanization and population growth have increased the food requirements in Sub-Saharan Africa including Kenya1. To meet this demand, various techniques including the use of fertilizers and pesticides have been introduced to increase food production and stave off serious livestock diseases2.\n\nKenya’s appetite for pesticides is high and is increasing exponentially3. Approximately 18,000 tonnes of pesticides were imported into the country in 2018 relative to about 7,600 tonnes in the late 90s1,3. Many of these pesticides have been banned, or their use is heavily restricted, in Europe and other developed jurisdictions due to their high toxicity towards the health of animals, humans, and the environment3. Despite European restrictions and interventions to use less hazardous products, some of the withdrawn pesticides are still in use in Kenya and continue to threaten the environment and health of Kenyans3. Dichlorodiphenyltrichloroethane (DDT), Dibromochloropropane (DBCP), Chlordimeform, Chlordane, Heptachlor, Toxaphene, and Ednrin are some organochlorines currently banned in Kenya1. Moreover, the use of Lindane, Aldrin, and Dieldrin is restricted in Kenya1.\n\nOrganophosphate and organochlorine pesticide residues have been detected in rain, rivers, groundwater, fish, soil sediment, rice, milk, tomatoes, beef, and camel meat in Kenya1,4–13. The health effects of pesticide exposure among formulators, repackers, and store workers in Nairobi have also been reported14.\n\nMilk is a food with immense nutritional importance to Kenyans as it provides proteins, calcium, iodine, phosphorous, and vitamins that promote the growth and development of infants2. Kiambu County is a leader in milk production while Isiolo and Laikipia Counties have the largest number of camel farmers and are associated with high levels of production of camel milk. However, little is known of the extent of pesticide residue contamination of the milk from these areas. This study aimed to determine the extent to which cow and camel milk collected from Kiambu, Isiolo, and Laikipia Counties is contaminated with pesticides residues. The human health risk assessment of pesticide residue contamination was also evaluated.\n\n\nMethods\n\nKiambu, Isiolo, and Laikipia County were selected as study areas. Kiambu County (-1010’0.01’’ S-36049’59.99’’E) has an area of 1679 m above sea level and is generally a dairy and tea zone area15. Sheep farming, horticulture and maize farming is also practiced. There are about 2.4 million inhabitants in Kiambu scattered over an area of 2450 km216. The county currently leads in cow milk production in Kenya17.\n\nIsiolo County (0021’16.63’’N-37034’55.85’’E) has a population of about 200,000 inhabitants and an area of 25,700 Km216,18. The main economic activity is livestock production and nomadic pastoralism is the major lifestyle of the inhabitants of this county18. Laikipia County (0001’0.01’’N-37004’22.19’’E) has a population of about 520,000 people and an area of about 8700 Km2. The map of the study area is shown in Figure 1.\n\nThe study was conducted between 2017 and 2018. Milk samples from 8 different wards of Kiambu, Isiolo and Laikipia were collected in 50 mL falcon tubes. A total of 90 cow milk and 82 camel milk samples were provided by farmers from collection centers for analysis. The samples were labelled (date, location, time), packed into ice-bags and transported to the Analytical Chemistry and Food Safety Laboratory-Directorate of Veterinary Services, Kabete for storage at -20 °C in the deep freezer before analysis.\n\nChemicals and reagents. Acetonitrile and Isooctane of high purity (99.9%) were purchased from Merck. Organophosphate standards (methacrifos, disulfoton, terbufos, chloropyrifosmethyl, tolclofosmethyl, fenchlorphos, malathion, tetrachlorvinfos, fenamiphos, chlorthiophos, profenofos, leptophos, and coumaphos) and Organochlorine standards (Alpha- Benzene Hexachloride [BHC], beta-BHC, Hexachlorobenzene, gamma-BHC (lindane), Delta-BHC, heptachlor, cis-chlordane, trans-chlordane, p’p-DDE, Alpha-endosulfan, dieldrin, Op’-DDD, Trans-nonachlor, chlorfenson, p,p’-DDD, Endrin, Beta-Endosulfan, p’p-DDT, Op’-DDT, Cis-Nonachlor, and mirex) were purchased as a gas chromatography multiresidue pesticide kit (100 μg/mL each in toluene, 1mL/ampoule) from Restec company. Quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction tubes, preweighed salts (6 g magnesium Sulphate, 1.5g sodium acetate) and 15 mL fatty samples AOAC tubes with ready to use salts (400 mg PSA, 400 mg C18EC, 1200mg magnesium sulphate) were all purchased from Agilent Technologies through Nesvax Innovations Ltd Nairobi, Kenya.\n\nPreparation of standard solution. A stock solution (1μg/mL) was prepared by weighing 200 μL of the multi residue pesticide standard into a 20 mL volumetric flask and toped up with isooctane. The standard stock solution was used to prepare various working concentrations through serial dilutions. The standard stock solution and other working solutions were stored in a refrigerator at 4°C. The standard for spiking experiment was obtained by transferring predefined volumes of family mixes from 150 μL–1500μL.\n\nExtraction of pesticide residues in milk. Milk samples were extracted using the QuEChERS technique. Briefly, 15 mL of whole milk was weighed into a 50 mL polypropylene centrifuge19,20. An appropriate amount of the pesticide spiking standard was added to the fortified blank sample and vortexed for 60 seconds, allowing 1 minute for the interaction of the matrix and the standard before extraction19,20. Acetonitrile (15mL) was added to each milk sample, capped, vortexed for 1 minute and pre-weighed salts (6g magnesium sulfate, 1.5g sodium acetate) were added and immediately shaken vigorously by hand for 1 minute to prevent the agglomeration of salts. The resultant mixture was centrifuged at 5000 rpm for 10 min at 4°C19,20, 6 mL of the supernatant layer were then transferred into a 15 mL tube containing 400 mg PSA, 400 mg C18EC, and 1200 mg magnesium sulfate. The resultant mixture was capped and vortexed for 1 minute then centrifuged at 5000 rpm for 10 minutes19,20. Following this, 1 mL of the extract was transferred into another tube, dried by nitrogen flow at 40°C, reconstituted with 1 mL of isooctane and filtered through disposable 0.45μm membrane filters into gas chromatography tandem mass spectroscopy (GC-MS/MS) auto sampler vials for GC-MS/MS analysis.\n\nGC-MS/MS. The pesticides residues were detected using a GC-MS-TQ8040 (Shimadzu, Japan) machine equipped with Shimadzu manufactured AOC-20s auto sampler and AOC-20i auto injector. The analytical capillary column was a ZB-5ms with a thickness of 0.25 μm, a length of 30.0 m, and a diameter of 0.25 mm. The column temperature was maintained at 50 °C for 1 minute then programmed at 25 °C/minute up to 125 °C, then finally 10 °C up to 300 °C for 3.50 minutes. This was held for 20 minutes. Helium (99.999% purity) was used as the carrier gas at a flow rate of 1.69 mL/min. The injection port temperature was 250°C and 1 μL was used as the injection volume with the spitless mode/purge flow was 5 mL/min. The ion source temperature was 200 °C, the interface temperature was 250 °C and the solvent cut was 1.5 minutes with a detector voltage 0.5 kV. Multiple reaction monitoring (MRM) was used to convert MS1 (parent ion) to MS2 (daughter ion). The retention time windows and base peak ions were designed for OCPs and OPPs. All pesticides were identified with specific ions and retention time and were quantified using the external standard method.\n\nRecovery studies were carried out using blank milk samples spiked at 10 ppb, 50 ppb and 100 ppb to determine the accuracy of the method. The amount of analyte which was recovered after complete sample extraction and processing was determined. The average recoveries of spiked OCP samples ranged from 73% to 97% and 78% to 100 % for OPPs. To determine the linearity of the method, a standard curve was constructed. Calibration curves of organophosphates and organochlorines were prepared using concentrations of 20 ppb, 30 ppb, 50 ppb, 100 ppb and 200 ppb. The calibration standards were prepared from a 1 ppm stock solution by using serial dilutions of the mixed OCPs and OPPs. Linearity was determined by regression analysis of the peak area against the concentration of the analyte and was expressed using the linear regression coefficient (R2). Generally, an R2 value of >0.998 is considered as evidence of an acceptable fit of data to the regression line. In this study the linear regression range was from 0.991–0.999.\n\nThe ability of the method to detect and separate OCPs and OPPs in the mixture without interference from other components in the mixture was determined. The selectivity of the method was determined when chromatographic peaks obtained from the mixture of the pesticide standard analysis showed the absence of interfering peaks. The lowest concentration at which OCPs and OPPs could be detected and also quantified was determined using the formula SLOD=SRB+3σRB, SLOQ=SRB+10σRB, where SLOD is the signal at the limit of detection (LOD), SLOQ signal at the limit of quantification (LOQ), SRB signal of the reagent blank, and σRB standard deviation of the reagent blank. According to the directives of the International Union of Pure and Applied Chemistry (IUPAC) and the American Chemical Society’s Committee on Environmental Analytical Chemistry the LOD for OCPs range from 0.1–0.3 ng/mL, the LOQ for OCPs range from 0.1–0.4 ng/mL, the LOD for OPPs range from 0.02–0.3 ng/mL, and the LOQ for OPPs range from 0.03–0.4 ng/mL. The relative standard deviation (RSD) was less than 3%.\n\nHuman health risk assessment. Dietary exposure, in the form of estimated daily intake (EDI), and the chronic/long-term hazard quotient (cHQ) are a measure of the health risk due to ingestion of milk contaminated with OCPs and OPPs. These were calculated for adults (aged above 18 years) and children (3–10 years) using the formula described by John et al.21.\n\ni.e. EDI=C∗FiBwt\n\nA body weight of 70 kg was used for adults (aged above 18 years) and 23 kg was used for children (aged 3–10 years) as recommended by the European Food Safety Authority22. C represented the average concentration of the chemical contaminants (ng g/) in the milk, Fi was the average daily intake and was based on the information retrieved from United States Agency for International Development-Kenya Agricultural Value Chain Enterprises (USAID-KAVES) dairy value chain analysis for adults (380 g) and Ogenche et al. for children (250 g)23,24. EDIs were compared with the acceptable daily intake (ADI) values25,26. The cHQ was calculated by the formula cHQ=EDI/ADI27.\n\n\nResults\n\nThe mean, median, range and percentage of samples contaminated with organochlorines (OCs) in raw cow and camel milk collected from Kiambu, Isiolo, and Laikipia counties28 are summarized in Table 1.\n\nMRL: Maximum residue limit; ppb: parts per billion; CS%: percentage of contaminated samples; EU: European Union; USDA: United States Department of Agriculture; BHC: Benzene Hexachloride; <dl: below detection limit; nr: not regulated; DDD: Dichloromdiphenyldichloroethane; DDT: Dichlorodiphenyltrichloroethane\n\nIn general, the values of OCs ranged from below the detection limit to 22.38 ppb (Table 1). The mean values ranged from 0.00 to 12.38 ppb, and the percentage of contaminated samples ranged from 0.00 to 93.85% (Table 1). The mean levels of heptachlor in cow milk collected from Kiambu County were above the maximum residue levels set by the Codex Alimentarius, and the European Union (EU) Pesticides Database (Table 1). The mean levels of heptachlor in camel milk collected from Isiolo and Laikipia Counties were above the maximum residue limits set by the Codex Alimentarius and the EU Pesticides Database (Table 1), 12/18 of the OCs evaluated are unregulated by the Codex Alimentarius, 10/18 are unregulated by the European Pesticides Database, and 15/18 are unregulated by the United States Department of Agriculture (USDA) (Table 1).\n\nThe estimated adult daily intake of OCPs in milk from Kiambu and Isiolo ranged from 0.00–0.08, while the estimated adult daily intake of OCPs in milk from Laikipia ranged from 0.00–0.10 (Table 2). The estimated pediatric daily intake of OCPs in milk from Kiambu ranged from 0.00–0.10 while the estimated pediatric daily intake of OCPs in milk from Isiolo and Laikipia ranged from 0.00–0.11 (Table 2). The adult cHQ of OCPs in milk from Kiambu and Laikipia ranged from 0.00–1000 while the cHQ of OCPs in milk from Isiolo ranged from 0.00–300.00 (Table 2). The pediatric cHQ of OCPs in milk from Kiambu ranged from 0.00–1000, the pediatric cHQ of OCPs in milk from Isiolo ranged from 0.00–400.00 while the pediatric cHQ of OCPs in milk from Laikipia ranged from 0.00–1100 (Table 2).\n\nADI: Acceptable daily intake; EDI: estimated daily intake; cHQ: chronic hazard quotient; BHC: Benzene Hexachloride; DDD; Dichlorodiphenyldichloroethane; DDT: Dichlorodiphenyltrichloroethane; nr: not regulated\n\nThe mean, median, range and percentage of samples contaminated with OPPs in cow and camel milk collected from Kiambu, Isiolo, and Laikipia counties are summarized in Table 3. In general, the values of OPs ranged from below the detection limit to 387.47 ppb (Table 3). The mean values ranged from 0.00 to 46.07 ppb, and the percentage of contaminated samples ranged from 0.00 to 93.18% (Table 3). 10/14 of the OPPs evaluated are unregulated by the Codex Alimentarius, 6/14 are unregulated by the European Pesticides Database, and 10/14 are unregulated by the USDA (Table 3).\n\nMRL: Maximum residue limit; ng/mL: nanogram per mL; CS%: percentage of contaminated samples; LOD: limit of detection; LOQ: limit of quantitation; RSD: Relative Standard Deviation; EU: European Union; USDA: United States Department of Agriculture; <dl: Below detection limit; nr: not regulated\n\nThe estimated adult daily intake of OPPs in milk from Kiambu ranged from 0.00–0.29, the estimated adult daily intake of OPs in milk from Isiolo ranged from 0.00–0.07 while the estimated adult daily intake of OPPs in Laikipia ranged from 0.00–0.09 (Table 4). The estimated pediatric daily intake of OPPs in milk from Kiambu ranged from 0.00–0.38, the estimated pediatric daily intake of OPPs in milk from Isiolo ranged from 0.00-0.46 while the estimated pediatric daily intake of OPPs in milk from Laikipia ranged from 0.00–0.12 (Table 4). The adult cHQ of OPPs in milk from Kiambu ranged from 0.00–33.33, the adult cHQ of OPPs in milk from Isiolo ranged from 0.00–3.00, and the adult cHQ of OPPs in milk from Laikipia ranged from 0.00–66.67 (Table 4). The pediatric cHQ of OPPs in milk from Kiambu ranged from 0.00–66.67, the pediatric cHQ of OPPs in milk from Isiolo ranged from 0.00-4.00, and the adult cHQ of OPPs in milk from Laikipia ranged from 0.00–66.67 (Table 4).\n\nADI: Acceptable Daily Intake; EDI: Estimated Daily Intake; cHQ: Chronic Hazard Quotient; nr: Not regulated\n\n\nDiscussion\n\nMilk may arguably be one of the most consumed food commodities in the world. The residual concentrations of OCPs and OPPs in two kinds of raw milk (cow and camel) available in Kenya were estimated in the present study.\n\nThe recorded results revealed that the percentage of cow milk samples contaminated with OCPs ranged from 0.00 to 93.85% while the percentage of camel milk samples contaminated with OCPs ranged from 0.00-96.15%. These ranges were higher than those detected in goat (75%), buffalo (75%), and cow milk (50%) samples by Raslan and colleagues in Zagazig city in Egypt29. However, the percentage of positive samples in cow milk reported in the current study were lower than the percentage of positive samples in buffalo and sheep milk marketed in Brazil (100%)30. In general, the values of OCPs ranged from below the detection limit to 22.38 ppb and the mean values ranged from 0.00 to 12.38 ppb. These values were lower than what was reported in human milk from Tanzania, cow, buffalo, and goat milk from Egypt, and goat milk and cheese marketed in Ethiopia and Ghana29,31–33. The results also showed that the detected concentrations of the OCPs were low when compared with the established maximum residue levels (MRLs) established by the Codex Alimentarius, the EU Pesticide Database and the USDA34,35. However, the mean levels of heptachlor evaluated in cow and camel milk collected in the study area were above the maximum residue limits set by the Codex Alimentarius and the EU Pesticides Database. These findings are in agreement with those of Omwenga and colleagues who reported high levels of heptachlor in farmed fish collected in the Kiambu and Machakos counties15. Heptachlor is a persistent organic pollutant (POP) which has been reported to be present in soil for up to 14 years after its initial application36. Like other POPs, it is lipophilic and poorly soluble in water and tends to accumulate in the body fat of humans and animals36. This organochlorine was banned in the US in the 1980s and is considered a potential carcinogen by the International Agency for Research on Cancer and the Environmental Protection Agency (EPA)36. Animals exposed to heptachlor during gestation and infancy were reported to have altered immune function, decreased body weight and some died37.\n\nBHC isomers and DDT were detected in some of the milk samples in the study area. The use of these pesticides was banned in Kenya on account of their persistence in the environment and toxicity to untargeted organisms15. Some of the isomers of BHC were initially used for seed dressing to protect crops against termites and for use in cattle dips. pp’-DDT was detected in 47.35% (Kiambu) of cow milk samples, and 30% (Isiolo) or 43.75% (Laikipia) of camel milk samples. These values were lower than the 50%, 75%, and 75% in cow, buffalo and goat milk samples in Egypt29. The presence of these OCPs in milk samples suggest previous use of these pesticides in agricultural activities in Kenya similar to what was observed in previous studies in Egypt (milk), Ghana (milk, yoghurt, and cheese), and Ethiopia (milk)29,31,32. Could farmers in the study area be using these pesticides illegally? Could their detection be related to previous application? These are pertinent queries that require further inquiry.\n\nHumans may be exposed to OCPs in a number of ways including polluted air, dermal ingestion, or via contaminated food and/or water29. The main source of human exposure to pesticides include foods such as milk and dairy products29,38. In the current study, the human dietary intake, EDI and risk assessment (cHQ) of pesticides were calculated using ADI values previously summarized by Dourson and Lu25,26. On the basis of this summary, the estimated daily intake and chronic/long-term hazard quotient values of only 11 out of 18 OCPs could be estimated. When cHQ values exceed 1, a health risk cannot be excluded27. The results of cHQ suggest that the consumption of cow’s milk by adults and children is alarming for endosulphans, dieldrin, heptachlor and DDT and the consumption of camel’s milk by adults and children is alarming for endosulphans, dieldrin, and heptachlor. A similar trend was observed in the case of heptachlor and dieldrin in Egypt and DDT in Arusha, Tanzania29,33.\n\nIt was established that the mean levels of all the 14 organophosphates tested were below the maximum residue limits set by the Codex Alimentarius, EU pesticides database, and the USDA. It may therefore be plausible that i) farmers in the study area may be adequately educated on the use of these pesticides, ii) the use of these pesticides may be generally low in the study area, or iii) proper handling of milk is practiced in the study area which minimizes contamination of the milk with the pesticides. However, the observation that cow milk registered higher mean levels of some organophosphate pesticides, including Chlorthiophos-2, Coumaphos, Fenchlorphous, Leptophos, Malathion, Profenefos, and Tetrachlorvinphos, relative to camel milk may have something to do with the fact that Kiambu county (where the cow milk was collected) is an agriculture intensive area and there may be a possibility of prior use of these pesticides relative to Isiolo and Laikipia counties (where camel milk was collected) which are mainly inhabited by pastoralists who may not be practicing large scale agriculture. Leaching and surface run-off could be another potential reason for the high levels of these organophosphates39.\n\nIn total, 15.34% of cow milk samples from Kiambu, 70.31% of camel milk samples from Isiolo and 43.75% of camel milk samples from Laikipia were contaminated with Malathion. This is in contrast to the 44% reported in raw buffalo milk collected in Assuit Egypt40. In general, the values of OPPs ranged from below the detection limit to 387.47 ppb. The mean values ranged from 0.00 to 46.07 ppb, and the percentage of contaminated samples ranged from 0.00 to 93.18%. A previous study on the levels of selected organophosphates in human colostrum and mature milk samples in Uttar Pradesh reported high ethion contamination in colostrum (23.1% or 6/26) and high levels of chlorpyrifos contamination in mature milk samples (50% or 4/8)41. The study further reported that the percentage chlorpyrifos contamination was 19.2% (5/26), dimethoate contamination was 3.8% (1/26) while 25.0% (2/8) of mature samples were contaminated with dimethoate, and 12.5% (1/8) of mature milk samples was contaminated with ethion41. Another study in Pakistan evaluated the dietary transfer of pesticides to dairy milk and its effect on human health. The study reported that about 40% and 20% of cow milk samples recorded residue levels of cypermethrin+chlorpyrifos and profenofos that was higher than their maximum residue limit as suggested by the World Health Organization42.\n\nThe primary objective of organizations such as the World Health Organization, the United States EPA, the Codex Alimentarius, and the EU Pesticides Database is to develop MRLs that are aimed at protecting the health of consumers while facilitating trade43. The MRLs are set at values which are not higher than those resulting from pesticide use in line with good agricultural practices (GAP)43. Most developing countries have not developed their own internal regulatory mechanisms for pesticides choosing instead to rely on the aforementioned organizations for guidance. In this context, it was worrying to observe that 10/14 of the studied OPPs did not have MRLs as per the Codex Alimentarius, 6/14 of the studied OPPs did not have MRLs as per the European Pesticides Database, and 10/14 of the studied OPPs did not have MRLs as per the USDA. This lack of regulation may be a huge pitfall as far as monitoring the levels of these chemicals is concerned.\n\nOrganophosphates have a high acute toxicity to target organisms4. However, they are not as persistent in the environment as organochlorines because they decompose into non-toxic products4. Notwithstanding, on the strength of the analyzed data, it may be inferenced that the health of children in the study area may be at a higher risk from organophosphates than adults. Data from Africa on this phenomenon is scant but a similar finding was observed in a study in India on the pesticide residues in peri-urban milk from Bhubaneswar, Guwahati, Ludhiana, and Udaipur in India44.\n\n\nConclusions\n\nThese findings suggest that OPP residue levels in cow and camel milk collected from Kiambu, Isiolo, and Laikipia counties are within acceptable limits. However, the levels of heptachlor in both Cow and Camel milk collected from these areas are above acceptable limits. The potential health risks with respect to chronic dietary intake of cow and camel milk in the study area cannot be excluded. The routine monitoring of OPP and OCP levels in milk is recommended to minimize risks to human health.\n\n\nData availability\n\nFigshare: Data for estimation and human health risk assessment. https://doi.org/10.6084/m9.figshare.16823788.v128\n\nThis project contains the following underlying data:\n\nData_Sheridan_F1000.xlsx (documentation of the levels of organophosphates and organochlorines in Kiambu, Isiolo, and Laikipia Counties)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors would like to acknowledge the contribution of members of staff including Dr. Kenneth Orengo, Shadrack Karanja, Yvonne, Catherine and Wesley stationed at the Analytical Chemistry and Food Safety laboratory at the Directorate of Veterinary Services for their technical assistance. Special gratitude to the Ministry of Agriculture, Livestock and Fisheries through the Directorate of Veterinary Services for partially funding the project (transport and logistics).\n\n\nReferences\n\nLalah JO, Yugi PO, Jumba IO, et al.: Organochlorine pesticide residues in Tana and Sabaki Rivers in Kenya. Bull Environ Contam Toxicol. 2003; 71(2): 298–307. PubMed Abstract | Publisher Full Text\n\nMaitho T: Pesticides residues in animal products in Kenya:organochlorine and organophosphorous insecticides in milk and body fat. 1978; [cited 2014 Aug 5]. Reference Source\n\nKaigwara P, Wandiga S, Lalah J: Pesticides in Kenya. 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PubMed Abstract | Publisher Full Text\n\nCommittee ES: Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data. EFSA journal. 2012; 10(3): 2579. Publisher Full Text\n\nUSAID-KAVES: USAID-KAVES Dairy Value Chain Analysis. Fintrac Inc, by the United States Agency for International Development, 2015. Reference Source\n\nOgenche CS: Milk Consumption Patterns and Nutritional Status of Children (24-59 Months) from Dairy and Non-Dairy Households in Nakuru County, Kenya. Egerton University; 2019. Reference Source\n\nDourson ML, Lu FC: Safety/risk assessment of chemicals compared for different expert groups. Biomed Environ Sci. 1995; 8(1): 1–13. PubMed Abstract\n\nLu FC: A Review of the acceptable daily intakes of pesticides assessed by WHO. Regul Toxicol Pharmacol. 1995; 21(3): 352–64. PubMed Abstract | Publisher Full Text\n\nOmwenga I, Kanja L, Zomer P, et al.: Organophosphate and carbamate pesticide residues and accompanying risks in commonly consumed vegetables in Kenya. Food Addit Contam Part B Surveill. 2021; 14(1): 48–58. PubMed Abstract | Publisher Full Text\n\nOkumu M: Data for estimation and human health risk assessment. figshare. Dataset. 2021. http://www.doi.org/10.6084/m9.figshare.16823788.v1\n\nRaslan AA, Elbadry S, Darwish WS: Estimation and human health risk assessment of organochlorine pesticides in raw milk marketed in Zagazig City, Egypt. J Toxicol. 2018; 2018: 3821797. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHeck MC, dos Santos JS, Junior SB, et al.: Estimation of children exposure to organochlorine compounds through milk in Rio Grande do Sul, Brazil. Food Chemistry. 2007; 102(1): 288–94. Publisher Full Text\n\nDarko G, Acquaah SO: Levels of organochlorine pesticides residues in dairy products in Kumasi, Ghana. Chemosphere. 2008; 71(2): 294–8. PubMed Abstract | Publisher Full Text\n\nDeti H, Hymete A, Bekhit AA, et al.: Persistent organochlorine pesticides residues in cow and goat milks collected from different regions of Ethiopia. Chemosphere. 2014; 106: 70–4. PubMed Abstract | Publisher Full Text\n\nMüller MHB, Polder A, Brynildsrud OB, et al.: Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human breast milk and associated health risks to nursing infants in Northern Tanzania. Environ Res. 2017; 154: 425–34. PubMed Abstract | Publisher Full Text\n\nEU Pesticides database - European Commission. [cited 2014 Jun 17]. Reference Source\n\nPesticides | CodexAlimentarius FAO-WHO. [cited 2014 Jun 18]. Reference Source\n\nAgency for Toxic Substances and Disease Registry: Heptachlor and Heptachlor epoxide. Division of Toxicology and Environmental Medicine. ToxFAQs - for Heptachlor and Heptachlor Epoxide. CAS # 76-44-8 and 1024-57-3. Reference Source\n\nAgency CEPFan AM, Alexeeff GV: Public Health Goal for Heptachlor and Heptachlor Epoxide In Drinking Water. 1999; 1–57.\n\nHassall KA: Biochemistry and uses of pesticides. Macmillan Press Ltd; 1990.\n\nSrivastava S, Narvi SS, Prasad SC: Organochlorines and organophosphates in bovine milk samples in Allahabad region. 2008. Reference Source\n\nShaker EM, Elsharkawy EE: Organochlorine and organophosphorus pesticide residues in raw buffalo milk from agroindustrial areas in Assiut, Egypt. Environ Toxicol Pharmacol. 2015; 39(1): 433–40. PubMed Abstract | Publisher Full Text\n\nSrivastava S, Narvi SS, Prasad SC: Levels of select organophosphates in human colostrum and mature milk samples in rural region of Faizabad district, Uttar Pradesh, India. Hum Exp Toxicol. 2011; 30(10): 1458–63. PubMed Abstract | Publisher Full Text\n\nIftikhar B, Siddiqui S, Rehman S: Assessment of the dietary transfer of pesticides to dairy milk and its effect on human health. Afr J Biotechnol. 2015; 13(3): 476–85. Publisher Full Text\n\nGuidelines for predicting dietary intake of pesticide residues (revised) Prepared by the Global Environment Monitoring System-Food Contamination Monitoring and Assessment Programme (GEMS/Food) in collaboration with Codex Committee on Pesticide Residues. 1997.\n\nGill JPS, Bedi JS, Singh R, et al.: pesticide Residues in peri-Urban Bovine Milk from india and Risk Assessment: A Multicenter Study. Sci Rep. 2020; 10(1): 8054. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "119332",
"date": "04 Mar 2022",
"name": "Agata Witczak",
"expertise": [
"Reviewer Expertise Food toxicology",
"Environmental toxicology"
],
"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 submitted for review concerns the levels of organochlorine (OCPs) and organophosphate (OPPs) pesticide residues in cow milk from Kiambu and camel milk from Isiolo and Laikipia. The human dietary intake and the potential consumer health risks were also evaluated in Kenya.\nThe results obtained are disturbing, because the levels of heptachlor in both Cow and Camel milk collected from these areas are above acceptable limits. The potential health risks with respect to chronic dietary intake of cow and camel milk in the study area cannot be excluded.\nI consider the results obtained at work as valuable and needed to correctly assess the health risk of consumers in Kenya.\nThe literature citation should be in accordance with the requirements of the publisher. Check the whole manuscript, please. Authors should carefully check for grammar, punctuation and sentence structure before submitting the revised paper.\nIt is recommended that this manuscript can be accepted for approval after minor revision.\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": "187925",
"date": "24 Aug 2023",
"name": "Cihat Özdemir",
"expertise": [
"Reviewer Expertise Food Technology",
"food sciences",
"milk and dairy products"
],
"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 thank all the authors who prepared and submitted the article titled \"Estimation and human health risk assessment of organochlorine and organophosphate pesticide residues in raw milk collected in Kenya\". This article is a useful study that determines the contamination levels of pesticides, which is still an important problem today. As it draws attention to an important problem, it reveals important information both scientifically and in terms of protecting public health. Thanks for your hard work and writing an interesting article on the estimation and human health risk assessment of organochlorine and organophosphate pesticide residues in raw milk collected in Kenya.\nThe article is well written. Experiments have been carried out in detail. I recommend it for indexing after minor revision. But the manuscript needs improvement, it would be better if the authors make some additions and revise it and resubmit it in an improved version just by correcting some errors in the draft.\nSuggestions for the authors are given below:\nThe letter c in the word 'cow' has been written sometimes capitalized and sometimes lowercase. The entire article should be written in lowercase letters.\n\nKeywords: camel milk should be added.\n\nIntroduction; very insufficient. General information is given little space. For example, how much cow and camel milk is produced in Kenya? Why are you looking for pesticides in camel and cow milk? Why are pesticides used so heavily in Kenya? In other words, which pest is more intense and which product does more damage? In what ways does pesticide contaminate milk? How does the pesticide that enters the human body cause harm, etc.\n\nMaterial and method: In line 4 under the heading 'Standard solution preparation': It should be 4 ± 1 °C instead of 4 °C. 'Sample collection and preservation' 4: The row should be -20 ±2 °C instead of 20 °C.\n\nDiscussion: The discussion has only been made with studies done in Africa, South America and some Asian countries. However, studies conducted in the USA and European Union Countries were not used. For example, I know that there are similar studies in Turkey. Including these studies in the discussion will increase the value of the article.\n\nSuggestions: In order to prevent these high pesticide levels that contaminate food, it can be recommended to focus on biological control of insects and pests.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-14
|
https://f1000research.com/articles/10-1037/v1
|
12 Oct 21
|
{
"type": "Method Article",
"title": "Reducing sources of variance in experimental procedures in in vitro research",
"authors": [
"Igor Fischer",
"Maria Victoria Martinez-Dominguez",
"Daniel Hänggi",
"Ulf Kahlert",
"Maria Victoria Martinez-Dominguez",
"Daniel Hänggi",
"Ulf Kahlert"
],
"abstract": "Background: Lack of reproducibility in preclinical research is a problem posing ethical and economic challenges for biomedical science. Various institutional activities from society stakeholders of leading industry nations are currently underway to improve the situation. Such initiatives usually attempt to tackle high-level organisational issues and do not typically focus on improving experimental approaches per se. Addressing these is necessary in order to increase consistency and success rates of lab-to-lab repetitions. Methods: In this project, we statistically evaluated repetitive data of a very basic and widely applied lab procedure, namely quantifying the number of viable cells. The purpose of this was to appreciate the impact of different parameters and instrumentations that may constitute sources of variance in this procedure. Conclusion: By comparing the variations of data acquired under two different procedures, featuring improved stringency of protocol adherence, our project attempts to propose guidelines on how to reduce such variations. We believe our work can contribute to tackling the repeatability crisis in biomedical research.",
"keywords": [
"reproducibility",
"standardization",
"quality control",
"in vitro research"
],
"content": "1. Introduction\n\nIn vitro work is the fundament of every wet lab project, both in academic research as well as in industry product development. With the recently emerging global move to reduce, refine, or replace animal research,1 the impact of cell model research on total research output is expected to increase even further.\n\nSome areas of biomedical research suffer from insufficient success rates to replicate or repeat core findings of previous observations. A survey amongst scientists recently highlighted that the community is not only well aware of this problem, but also confirmed that personal experiences in this issue are common.11,2,12 A standard in vitro method for drug development or genetic studies is the quantification of cellular growth over time, under different micro-environmental conditions. For this basic assay, on which to some extent almost all global oncology blockbusters of today’s market are based on, inconsistencies in repeating research results have been noticed.8,6,13 In response this this, leading science organizations, in cooperation with respective policy makers, scientific publishing houses, and other society stakeholders, have initiated institutionally funded campaigns to tackle these issues, such as the cancer reproducibility project, to mention only one.4,15 Moreover, improved and increased standardization in wet lab research is proposed to be a powerful strategy to increase academic science repeatability.3,9,5\n\nAccurate cell counting is crucial in laboratories for research purposes, medical diagnosis and treatment. As an example, a precise knowledge of the number of cells in blood samples of a patient could be crucial in the determination of the cause of disease. If the analytical performance is uncertain or deviates from other methodologies, the method should not be implemented.\n\nCurrently, the main methods for cell counting are manual counting or automated cell counting. Each of these specific methods comes with its advantages and disadvantages. On one hand, manual counting relies on the experimenter, microscopes and counting chambers, seemingly causing a higher error in repeatability, which only increases with the number of samples to analyze. Additionally, it is laborious and time-consuming.16,7 Increasingly, manual counting is being replaced by automated cell counting, as its in the case of blood cell counting, where it present several additional difficulties, such as the distinguishing in size or morphology of blood cell types, which is crucial for a correct identification.14\n\nAutomated counting is fast, efficient and does not include a human error beyond the process of sample preparation. Nevertheless, accuracy and sensitivity are lost after a long-time use of the machine and more and more often calibration steps are needed.7 In addition, cell automatic counting is not well suited for volumes lower than 105 and larger than 107 cells, under or overestimating the cell number and therefore the clinical reliability.\n\nIn this study we investigate the repeatability and variance of results in experiments involving human operator and automatic instrumentation-based quantification of cells. In order to quantify the variance and identify its sources, we set up an experiment in preparing the stem cell suspension and counting the cells in it, both viable and dead. Our experiment included three researchers with different amount of experience, who prepared and counted viable and dead tumor stem cells. Moreover, by comparing the variances in data acquired under two different procedures, our project attempts to propose guidelines how to reduce them. We believe our work supports ambitions to tackle biomedical repeatability crisis by promoting the power of standard operating procedures to reduce variance in early stage wet lab experimentation.\n\n\n2. Material and methods\n\nAs our cell model, we selected a state of the art 3D cell culture (the familiar brain tumor stem cell line NCH644 generously provided by Prof. Herold-Mende, Heidelberg, Germany). The cells were cultured as suspension under neurosphere conditions as described elsewhere.10 After incubation, each experimenter prepared a cell suspension for counting, by the standard wetlab procedure (Supplementary file SOP-cellPreparation.pdf). A total volume of 1 ml of cells from each suspension was taken for counting by every researcher: the one who prepared the cells and the two other scientists. Compared to the first run, essential specifications that were added to the guidelines to perform the experimental procedure are: timing of each step, amount of trypsin times of pipetting for cell separation and, most importantly, familiarization with the procedure. The cells, viable and dead, were counted in two different ways: manually, under the microscope, and automatically using a specialized cell counting machine.\n\nHuman operator counting: Three researchers with different levels of wetlab experience were involved in the experiments: A senior, experienced researcher (UKD), somewhat out of daily practice; a MS student of molecular biology (VM) who works in the wetlab on an almost daily basis; and a computer scientist and a complete novice to wetlab research (IF). For manual counting, the haemocytometer, also known commonly as Neubauer-improved chamber with 0.1 μl capacity was used. The viable (defined as white) and dead (blue) cells were counted under the microscope in four quadrants using brightfield microscopy with a 10× objective. Each researcher counted cells in two different samples (two fields of the same Neubauer chamber) from the same suspension. Each sample was counted by all three researchers, resulting in 48 counts per suspension: 3 researchers × 2 samples × 4 quadrants × 2 types of cells, viable and dead. As three different suspensions were prepared, this led to 144 different counts per experiment.\n\nThe cell concentration (cells/ml) was computed by multiplying the number of cells, summed over the quadrants, by 10,000 (=1000μl/ml/0.1 μl) and dividing by the number of quadrants (4).\n\nAutomated counting was done using Guava® Muse® Cell Analyzer, Luminex second generation, SN 7200121445, Luminex, Germany, using Muse® Count & Viability Kit (MCH600103) according to manufacturer descriptions. Both the viability and the cell size (fragmented dead cells versus alive cells) parameters were left as default. Each researcher's cell suspension was measured three times in a row both with the Neubauer chamber and the Cell Analyzer.\n\nThe above experiment was performed twice: first, without explicitly establishing the standard operating procedures (SOPs) and, weeks later, by adhering to SOPs written for that purpose as part of the labs quality control system. The SOP can be found in the supplementary data of this article (Supplementary data File SOP-cellCounting.pdf).\n\nThe homogeneity of cell counts in the Neubauer chamber was checked using the χ2-test. Linear regression was used to model viability of cells over time. Uniformity of cell counts between the three researchers was tested using ANOVA and post-hoc t-test. F-test was used for comparing variances in the data. All computations were performed in Python, using numpy and scipy.stats modules.\n\n\n3. Results\n\nIn the first experiment, without the SOPs, the NCH-644 cells from which the first suspension was made were not viable enough and kept dying rapidly during counting. Consequently, the cell counts among the researchers differed significantly, from around 500,000/ml at the beginning of the counting down to 140,000 at the end (p<10−20, Figure 1). For further analysis, we excluded this first suspension and used a different cell culture to prepare new solutions.\n\nIn the repeated experiment, done according to the SOPs, all solutions remained stable with time. The ordinal count number (1st counting, 2nd counting etc.) is shown on the x-axis and the logarithm of the number of cells counted on the y-axis.\n\nTo quantify the homogeneity of the suspensions, we performed χ2-test of homogeneity of manual counts in the four quadrants, separately for each counting researcher. Altogether, inhomogeneous cell numbers (p<0.05) were found in 25% of the cases (9 out of 36). Comparing cell counts between different researchers, separately for each quadrant, showed no significant differences, except in one case when one researcher (IF) counted significantly more dead cells (p<10−4).\n\nUsing manual counting, the total cell concentration, viable + dead, varied between 105,000 and 192,500 cells/ml (mean = 137,000, sd = 28,000). Automated counting produced significantly higher numbers (p=0.0013): between 163,700 and 317,500 cells/ml, with mean = 271,100 and sd = 55,900. Despite the difference in counts, the coefficient of variation (cv = sd/mean) was almost identical for manual and automated counting, 0.205 vs. 0.206, respectively. In both cases, the mean counts were similar, regardless of the researcher who prepared the solution (p=0.57 for manual counting and p=0.41 for automated counting). But, the solution prepared by VM was significantly more homogenous, having lower variance than the one prepared by IF (F-test, p=0.013).\n\nA similar pattern, with an even greater discrepancy between manual and automated counting could be observed when taking only viable cells into account. For manual counting, the variance of the viable cells is not as large as for the total number of cells. Interestingly, automated counting found a very low variance of dead cells. With manual counting, the number of viable cells varied between 65,000 and 135,000 cells/ml, with mean = 105,200, sd = 18400, and cv = 0.168.\n\nIn the second run of the experiment, performed according to the SOPs, all cells were viable and could be considered for counting. it was observed that the homogeneity of the cell counts in different quadrants of the Neubauer chamber did not improve: We again encountered 9 out of 36 cases where the numbers of cells in the quadrants differed significantly (p < 0.05), according to the chi-squared test.\n\nComparing the counts in the two runs, for the two researchers whose cells were viable in the first run, performing the experiment by the SOPs significantly reduced the variance in the counts, both manual and automated. In the first run, the coefficient of variation (cv) for the manual count was in the range 0.16 to 0.24, and 0.07 to 0.30 for the automated counting. In the second run, the cv for manual counting fell to 0.05 to 0.07, and to 0.02 to 0.04 for the automated counting (Figures 2 and 3).\n\nTo ensure comparability between experiments, the y-axis shows the cell count scaled by the mean of the cell count in the respective experiment.\n\nAgain, as in Figure 2, the cell counts are scaled to ensure comparability.\n\nSurprisingly, manual and automated counting led to significantly different numbers, in both runs (Figure 4). While for the manual counting the total cell numbers were consistently in the range 100,000 – 200,000, the counting machine found 150,000 – 300,000 in the first run and 250,000 – 550,000 in the second. Another point worth noticing is that the number of live and dead cells varied between the machine operators. As the machine requires manual adjustment of threshold for detecting dead cells, we believe this to be one source of variation.\n\nCell Analyzer consistently counts more cells than the researchers using the microscope.\n\n\n4. Discussion\n\nGiven the very wide dissemination of the applied experimental procedure, this project presents—to the best of our knowledge—the hitherto first dedicated calculation of sources of variance on cell quantification between automated and manual cell counting in suspension stem cell lines. Although the setup per se is rather simple nature, we are convinced the drawn conclusions are of significance for the general readership.\n\nResearch laboratories need to do cell counting on a daily basis. Parameters as precision, accuracy, time-consumption and reliability are critical for a good performance. With this perspective, this study compared two forms of a widely used basic lab procedure: cell quantification.\n\nTo evaluate the performance of automated and manual counts, statistical analyses have been made to address the accuracy and repeatability to benchmark one against other method. Careful preparation of the cell culture proved critical. In our case, the experienced researcher (UDK) noticed already during counting that the numbers of live cells were decaying, but this experiment was also specifically set up to identify such problems. The suspicion was confirmed in further counting by the other two researchers (VM, IF). However, due to time and personnel constraints, multiple counting of a same probe is uncommon. It is therefore conceivable that a less experienced or less attentive (unsuspecting) researcher would fail to notice this problem. Due to exponential cell growth, variations in the starting number of cells grow much larger after incubation. For our manual counting of viable cells, the initial variation of 16% would increase to 44% after three mitoses. The used cell model is in general range for cell proliferation index of many cancer cells (18–36 hours) and therefore our results may be representable for scenarios when working with other cell models. When the manual countings between different researchers was compared between quadrants, one researcher (IF) counted significantly more dead cells (p<10−4). The other two researchers’ guess is that he, due to lack of experience, counted cell debris as dead cells. Adhering to the SOPs led to more consistent results. The second time, the procedure was better prepared and performed more quickly, this indicates that the duration of the experiment plays a role.\n\nIndependently of the human operator that prepared the initial cell suspension, we noticed severe difference in absolute quantification of cells (viable and dead) between manual and automatic counting. From our data, this somewhat surprising outcome cannot be explained scientifically. Although our instrument handling and counting setup was performed according manufacturer instructions, it remains possible, albeit somewhat speculative, that the gating setting caused the Cell Analyzer to misclassify debris or cell doublets as single cells. Moreover, comparing quantification outcomes based on biological assays that exploit same property of the cells (cell membrane integrity), but use different reporter signal (human counting is based on colorimetric, whereas an automatic counting is based on fluorescence), is likely another cause of the differences. Since in vitro cell growth assays usually compare different genetic conditions or environmental stressors, absolute quantification is less important than relative quantification between different test conditions. As long as only relative cell growth/cell dying is of concern, experiments can be set up manually and checked for result stability. Automated counting is not an impediment as long as the same counting method is used when comparing data. This is especially important in lab-to-lab validation, to ensure comparable results.\n\nHowever, absolute cell number is important in order to define optimal cell plating density at the beginning of the experiment: Sufficient, but not too dense cell-cell contact/confluence grade is a critical factor which impacts the cells’ growth rate, so cells need to be plated in a density that allows exponential growth under control conditions over the entire period of the experiment. Therefore, we suggest to acquire an individual standard growth rate for each cell model to be studied. Our data show that it is highly relevant that the exact same procedure—counting for plating and indirect method for readout at the end of experiment such as MTT/cell TiterGlo—is applied for this “preparatory analysis” as for the actual experiment. Lastly, and of well-known nature, our experiment ignores benefits of automatic counting in the context of larger sample series, such as less burden on human operator concentration as well as acceleration of the experiment.\n\nImportantly, adhering the execution to the SOPs, which define maximum time of the execution, familiarization with the SOP, addition of trypsin for a specific time in the incubator and specification of number of times of pipetting for cell separation, led to more stable, in our viewpoint consistent and repeatable results. Although our experiments were performed on a small scale, adhering to the SOPs showed a significant improvement in the stability of the results. We therefore suggest devising such SOPs and enforcing the adherence in wetlab research.",
"appendix": "References\n\nExpanding the 3r principles. EMBO Rep. 2017; 18(9): 1490–1492. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaker M: 1,500 scientists lift the lid on reproducibility. Nature. 2016; 533(7604): 452–454. PubMed Abstract | Publisher Full Text\n\nBaker M: How quality control could save your science. Nature. 2016; 529(7587): 456–458. PubMed Abstract | Publisher Full Text\n\nBaker M, Dolgin E: Cancer reproducibility project releases first results. Nature. 2017; 541(7637): 269–270. PubMed Abstract | Publisher Full Text\n\nBegley CG, Ellis LM: Drug development: Raise standards for preclinical cancer research. Nature. 2012; 483(7391): 531–533. PubMed Abstract | Publisher Full Text\n\nBen-David U, Siranosian B, Ha G, et al.: Genetic and transcriptional evolution alters cancer cell line drug response. Nature. 2018; 560(7718): 325–330. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGlasser L, Murphy CA, Machan JT: The clinical reliability of automated cerebrospinal fluid cell counts on the beckman-coulter lh750 and iris iq200. Am J Clin Pathol. 2009; 131(1): 58–63. PubMed Abstract | Publisher Full Text\n\nHaibe-Kains B, El-Hachem N, Birkbak NJ, et al.: Inconsistency in large pharmacogenomic studies. Nature. 2013; 504(7480): 389–393. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHewera M, Nickel AC, Knipprath N, et al.: An inexpensive and easy-to-implement approach to a quality management system for an academic research lab. F1000Res. 2020; 9: 660. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKahlert UD, Maciaczyk D, Doostkam S, et al.: Activation of canonical wnt/beta-catenin signaling enhances in vitro motility of glioblastoma cells by activation of zeb1 and other activators of epithelial-to-mesenchymal transition. Cancer Lett. 2012; 325(1): 42–53. PubMed Abstract | Publisher Full Text\n\nLithgow GJ, Driscoll M, Phillips P: A long journey to reproducible results. Nature. 2017; 548(7668): 387–388. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMacleod MR, Michie S, Roberts I, et al.: Biomedical research: increasing value, reducing waste. Lancet. 2014; 383(9912): 101–104. PubMed Abstract | Publisher Full Text\n\nPrinz F, Schlange T, Asadullah K: Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011; 10(9): 712. PubMed Abstract | Publisher Full Text\n\nSandhaus LM: Is the hemocytometer obsolete for body fluid cell counting? Am J Clin Pathol. 2016; 145(3): 294–295. PubMed Abstract | Publisher Full Text\n\nWen H, Wang H-Y, He X, et al.: On the low reproducibility of cancer studies. National Sci Rev. 2018; 5(5): 619–624. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang M, Gu L, Zheng P, et al.: Improvement of cell counting method for neubauer counting chamber. J Clin Lab Anal. 2020; 34(1): e23024. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "98466",
"date": "08 Nov 2021",
"name": "Kapil Dave",
"expertise": [
"Reviewer Expertise Biophysics and Computational Biology",
"Molecular Dynamics simulations",
"in vitro experiments",
"Protein misfolding and aggregation in complex environments"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this manuscript, the authors have demonstrated that following and promoting a standard procedure for conducting a wet lab experiment results in lower variation. This approach of documenting and following a standard protocol can help alleviate the lab-to-lab repeatability problems. Overall, the data supports the conclusion. However, the authors should rewrite the discussion section (details below) for the readers to follow the results, along with addressing the comments below:\n\nPage 3, \"distinguishing in size or morphology of blood cell types\": Please remove the \"in\" from this sentence. Please carefully proofread the article to correct similar errors in the paper and avoid using ambiguous English language.\n\nPage 3, \"A senior, experienced researcher (UKD)\": the term UKD is used in the text, while in the figure, legend, and caption \"UDK\" is used. Please use consistent terminology across the manuscript.\n\nFigure 1, SOP=False: The author should clarify why the UDK operator only showed high variation in viable cell count, whereas an operator with no prior wet-lab experience (IF) had lower variability with the same suspension.\n\nPage 4, Section 3 \"Consequently…… For further analysis, we excluded this first suspension and used a different cell culture to prepare new solutions\": it is not clear from this paragraph which \"new solutions\" that were prepared were made by which human operator.\n\nPage 5, \"A similar pattern, with an even…. cv = 0.168\": the paragraph is vague and not clearly written, authors, should re-write to make it clear to the readers. I suggest making an apples-to-apples comparison between counting viable cells (manual vs automated) and Dead cells (manual vs automated).\n\nPage 6, Section 4: Please rewrite the paragraph \" Research laboratories ….. Cell quantification\" - it's not clear what two forms the authors are referring to in this paragraph.\n\nPage 7, \"The second time, the procedure was better prepared and performed more quickly, this indicates that the duration of the experiment plays a role”: Authors should clarify or provide more evidence to support this statement. Performing an experiment faster doesn’t always guarantee less variation (shows familiarity), rather, following the SOP diligently could help reduce variation.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\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": "7641",
"date": "07 Jan 2022",
"name": "Igor Fischer",
"role": "Author Response",
"response": "Thank you very much for careful reading and providing constructive suggestions to imporve the article. 1. We've corrected the error, carefully proofread and extensively edited the article. 2. We corrected the typo and ensured consistent usage of abbreviations. 3. In the caption to the Figure 1, we clarified that the high volatility was observed in the first solution that was prepared (\"the first prepared\" inserted). In the text (\"Results\", p.4), we added the sentences \"Although the way the experiment was conceived did not allow for establishing the cause with certainty, we assume that a toxic agent - perhaps the alcohol used for cleaning the equipment - somehow contaminated the culture\" and \"Special care was taken to avoid contamination\". 4. We clarified the operators and the order in which they prepared the solutions: \"first suspension ... (prepared by UDK)\" and \"The second solution was prepared by VM and the third by IF\" 5. We rewrote the paragraph as suggested and included numbers for dead cells. 6. We rewrote the paragraph as suggested, to read: \"Research laboratories need to perform cell counting on a daily basis. Precise workflow, accurate execution and reliable measurements within the time constraints are critical parameters for achieving good performance. With this perspective, this study compared two forms of a this widely used basic lab procedure, manual and automated counting.\" 7. We added a clarification, so that the paragraph now ends with: \"Although execution speed is not by itself an indication of quality – indeed, it might even be a sign of rushing through the experiment – in case of living cells which might be dying as the experiment is performed, completing it in a timely manner at least ensures that the conditions didn’t change too much between the beginning and the end. Our results seem to confirm this assumption.\""
}
]
},
{
"id": "98468",
"date": "15 Dec 2021",
"name": "Piotr Walczak",
"expertise": [
"Reviewer Expertise Image-guided drug delivery to the brain"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript describes a very simple but widely used technique - counting viable vs. dead cancer cells with the goal of improving reproducibility of the method. I suggest correcting the following:\nFor cell preparation, please specify what the total volume was from which 1ml was drawn three times.\n\nWas there mixing involved before/after or in between the individual sampling to avoid sedimentation?\n\nIt is not clear what the authors mean by \"cells were dying rapidly during counting\". If that was the case, it indicates some unspecified error which was corrected when they used their specific SOP. They should at least attempt explaining what may have caused this unexpected result.\n\nDifferences between the \"casual\" and SOP-based counting should be described at least briefly in the main manuscript, not only in the supplementary data.\n\nPhotographic images of cells during counting with markings what was considered as live vs. dead cells for both manual and automatic methods would be helpful.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1037
|
https://f1000research.com/articles/10-1094/v1
|
28 Oct 21
|
{
"type": "Research Article",
"title": "Proactive measures to eradicate Malaysia’s poverty in IR4.0 era: a shared prosperity vision",
"authors": [
"Darshana Darmalinggam",
"Maniam Kaliannan",
"Magiswary Dorasamy",
"Maniam Kaliannan",
"Magiswary Dorasamy"
],
"abstract": "Background: In the country’s shared prosperity vision, Malaysia aspires to uplift the bottom 40% household income group (B40) by addressing wealth and income disparities. By 2030, the nation seeks to eradicate poverty through the provision of employment opportunities and career progression plans. A grey area between the nation’s aspirations and actions in practice can be observed because the goals have not been achieved despite numerous efforts aimed at the upliftment of the B40 group. The nation is still way behind its targeted outcomes despite various policies being implemented, which could be attributed to the mismatch between government policies and that of organisational practice. Thus, this study explores the rationale of strategic government intervention in managing B40 talent in the IR4.0 era. Methods: A general qualitative inquiry method that used 11 semi-structured interviews was carried out with representatives of Malaysia’s policy makers’, training providers, and trainees. All Interview questions centred around measures, importance and outcomes of B40 youth training from a multi-stakeholder perspective. Data were thematically analysed in five stages using NVivo. Results: Training, which includes IR4.0 era digital skills, is the key to uplifting the B40 youth to eradicate poverty. Proactive measures are imperative in the success of B40 youth training towards poverty eradication. Conclusions: This study contributes to the existing literature and helps practitioners by addressing the current gap in Malaysia’s aspirations versus organisational practice. Stakeholders should formulate proactive strategies to ensure that the right trainees are matched with the right training providers and government policies. A linkage between government policies and industry requirements needs to be established as opposed to the present discontinuity. A structured training needs analysis should be applied through a collaboration between industries and governments. Then, B40 individuals commonly found in lower-level positions can be pooled into the career pathway towards a shift into M40.",
"keywords": [
"Malaysia",
"poverty",
"equality",
"training needs analysis",
"multi-stakeholder",
"B40",
"youth",
"proactive"
],
"content": "Introduction\n\nIn the country’s shared prosperity vision 2030, Malaysia aspires to uplift the bottom 40% household income group (B40). Accordingly, the shared prosperity vision aims to (1) develop all citizens in various levels through economic restructuring of full community participation towards a more progressive, knowledge-based and highly valued community, (2) address income and wealth disparities through eradicating inequalities and ensuring that no one is left behind and (3) attaining a united, prosperous and dignified nation through nation-building in becoming Asia’s economic centre.9 By 2030, the nation seeks to eradicate poverty through the provision of employment opportunities and career progression plans. However, a grey area between the nation’s aspirations and actions in practice towards poverty eradication can be observed.1 Poverty eradication in Malaysia refers to those in the B40 group. The goals have not been achieved despite numerous efforts aimed at the upliftment of the B40 group. The nation is still significantly behind its targeted outcomes despite various policies being formulated, which can be attributed to the mismatch between government policies and organisational practice. To re-match the two aspects, Malaysia could focus more attention on inclusive talent development practices targeted at the B40 youth. This inclusive youth training approach has been supported in past literature.10 The B40 group represents the poverty that Malaysia is currently facing. Many of the B40 group households tend to have lower-level job positions or are unemployed because of mismatches or lack of the right knowledge, skills, abilities and attitude. The more relevant knowledge, skills and abilities in this industrial revolution (IR) 4.0 era include training programs that focus on data sciences, green accounting, and forensic economics.11 Thus, to eradicate poverty in the long run, Malaysia should uplift the B40 youth group because they are the future generation that would determine the poverty level in Malaysia. Once they are uplifted into the middle 40% household income group (M40), poverty would be eradicated for good as they grow up to become adults or parents of the M40 group. Accordingly, this study aims to explore the rationale of government intervention in managing B40 youth talent via training in this IR4.0 era. The following research questions guide the study.\n\n\n\nResearch question 1: To what extent is training important in uplifting the B40 youth in line with poverty eradication?\n\nResearch question 2: What are the proactive measures and to what extent are they crucial to the success of B40 youth training towards poverty eradication?\n\n\nMethods\n\nA general qualitative approach using interviews from an interpretative perspective was used in this study.2 The researchers believe that the knowledge on proactive measures to uplift the B40 youth is interpreted from the results of the study. The entire study took place within 2 years (2019-2021). Details on the research design are provided in Table 1. The research idea was outlined by researcher 1, a master’s student, and researcher 2, a lecturer (associate professor), who has vast experience in teaching human resource management modules and has undertaken several other research projects concerning talent management. Researcher 3, also a lecturer (associate professor), is an NVivo software expert which was used for data analysis. However, the suitability of software usage was revisited post-data collection, using a methodological reflexivity approach.3 Researchers 1 and 3 are females and researcher 2 is a male, and thus no gender bias is thought to be evoked throughout the study. Overall, the study was informed by the researchers’ understanding, knowledge and experience on the subject matter, reflecting ontological reflexivity to a certain degree.\n\n\n\no Interpretative (Inquiry and investigation are prime method)\n\n\n\no General Qualitative Inquiry Method\n\n\n\no Interviews (multi-stakeholder groups)\n\n\n\no Unit of analysis: Individuals\n\no Respondents: Representatives from policy makers, trainers, and trainees\n\no Sampling Method: Purposive Sampling Method\n\n\n\no Thematic Analysis – 5 Stages (become familiar with data, generate initial codes, search for themes, review themes, define themes)\n\no Word Frequency Analysis, Word Cloud, Mapping of Themes to Con\n\n\n\no Credibility – Research findings are plausible information drawn out from participants’ original data and is a correct interpretation of the participants’ original views.\n\no Transferability – The researchers facilitates transferability judgement by a potential user through thick description.\n\no Dependability – Participants’ evaluation of the findings, interpretation and recommendations of the study are all supported by the data received from participants.\n\no Confirmability – Data and interpretations of the findings are not figments of the inquirer’s imagination, but clearly derived from the data.\n\no Reflexivity – Researchers constantly self-reflected oneself as a researcher (own biases, preferences, preconceptions), and the research relationship (relationship to the respondents), and how the relationship affects participants’ answers to question\n\nPurposive random sampling4 was used to gain insights from three stakeholder groups namely policymakers, training providers and trainees to obtain a multi-stakeholder perspective on B40 youth upliftment via training. Training providers provide various trainings including entrepreneurial, electrical, computer, and wiring areas which mainly target Malaysian youth. Policymakers were approached via emails to the relevant ministries which then directed the researchers to representatives in charge. Only trainees who had surpassed six months post-training completion were approached through a training provider. Trainees approached underwent skill-based training programmes on various courses including computer, electrical and wiring areas. These B40 youth trainees were given monetary compensation for their time while representatives from the policymakers and training providers voluntarily participated in the study. All potential participants who were approached took part. A total of 11 participants were attained, surpassing the suggested sample size of 4 to 10 for case studies.5 No prior relationship was established with participants. Approval for data collection was obtained from the University of Nottingham Malaysia ethics committee and Nottingham University Business School Research Ethics Committee (ref number: NUBS-REC-2021-11). All participants and respective higher authorities for each stakeholder group were orally asked for consent, their confidentiality guaranteed, and the interviews were only conducted upon their agreement. Oral consents as such are allowed under NUBS REC’s pre-approved protocol regulations.\n\nOne-on-one semi-structured online interviews were conducted between 15 April and 1 May 2021 by researchers 1 and 2. Semi-structured interviews were preferred because the study was exploratory.6 Interview questions centred around measures, importance and outcomes of B40 youth training (refer to Table 2 for details). For example, details of training courses, benefits of training courses, challenges faced throughout training, and nation’s strategic plan on B40 youth training. Probe questions were catered towards specific group of stakeholders accordingly. The interview schedule can be found as Extended data.13 Subsequently, data were transcribed and analysed using NVivo software (version released in March 2020) for a month. A pilot interview was conducted with the third researcher to ensure that the questions are clearly understood by the interviewees. No changes were made to the interview guide as deemed appropriate. Before the interviews, every interviewee was provided with a rough question guide on areas the researchers would cover in the interview. At the start of the interview session, participants were briefed on the researchers and the study area. Each interview session varied between 40 minutes to 1 hour and interviews were not repeated. All interviews were audio-recorded through Microsoft Teams or Google Meet platforms’ recording functions upon consent from interviewees. Occasionally, issues with the internet connection disrupted the flow of the interview sessions. Nevertheless, the researchers managed to cope with the situation and continue where they left off. The two applications were used to conduct the interviews based on interviewees’ preferences and comfort. Probing questions were used whenever the researchers needed to gain in-depth insights from the participants. Field notes were recorded during the online interview sessions as a backup and were cross-checked against transcriptions for accuracy. Details of the 11 interviewees can be found in the results section of the report.\n\n\n\n1) To what extent is training important in uplifting the B40 youth in line with poverty eradication?\n\n\n\no What is the success rate of the training like?\n\no What are the benefits of training?\n\no Do you agree that training has had a positive impact on your lives?\n\n\n\no Trainer\n\no Trainee\n\n\n\n2) What are the proactive measures and to what extent are they important in the success of B40 youth training?\n\n\n\no What are the challenges faced in B40 youth training and what are your action plans?\n\no From a strategic perspectives, what is your strategic plan in order to maximise benefits and minimise challenges of training programme, upskilling, reskilling or employment, or entrepreneurship to the B40 youth especially?\n\no What are the interests of the B40 youth group?\n\no What kind of training do the B40 youth group want/need?\n\no How do you identify and pool these B40 youth participants?\n\no In your framework/governance, is there any particular emphasis on B40 youth?\n\n\n\no Trainer\n\no Trainee\n\no Policy makers\n\nAll interviews were transcribed word-for-word manually while maintaining the anonymity of interviewees. Pseudo names were assigned to each participant while categorising them in their respective stakeholder group. Accordingly, policymakers were referred to as PolicyMaker_1, PolicyMaker_2, PolicyMaker_3, and PolicyMaker_4; training providers’ were referred to as Trainer_1, and Trainer_2; and trainees were referred to as Trainee_1, Trainee_2, Trainee_3, Trainee_4 and Trainee_5. All transcriptions were coded using NVivo software with occasional word cloud queries based on the question type for a thematic analysis method.5 Verbatim statements were also chosen for several questions through the software. The third researcher conducted the analysis using the software along with the first researcher’s contextual input. The third researcher proceeded to make inferences based on the analysed data. Member checking was conducted during and post interviews.7 Answers to questions were repeated for confirmation from interviewees and findings of the report were shared with the interviewees. None of the interviewees suggested amendments to the data or findings reported. As detailed in Table 1, several validity and reliability measures for qualitative research studies were followed.7\n\n\nResults\n\nEach interview began with a brief demographic check. Details of the participants’ designations and roles are outlined in Table 3.\n\n\n\no Strategic initiative department\n\no Provides training opportunities for registered and non-registered employers\n\no Have funding for SMEs, B40 groups, and entrepreneurs\n\no Traces study/output assessments post-training\n\no Funds for B40: entrepreneurship, employment, reskilling and upskilling\n\n\n\no Training placement centre department\n\no In charge of employment opportunities\n\no Implements various initiatives based on funding and various target groups\n\no Works together with strategic initiative department\n\n\n\no Vice president for SME accounts\n\no Customer outreach\n\no Provides consultation and advisory towards SME employers in central region regarding training requirements\n\n\n\no Strategic division\n\no Similar pillar of strategic initiative department\n\n\n\no Works with women and youth in training provision\n\no Provides training with certificates approved by ministry of human resources\n\no Mostly entrepreneurship development programmes on marketing, digital marketing, financial literature, unique selling point, how to sell products, specific skills sharpening\n\n\n\no Manager of training institute under human resources ministry\n\no Provides diploma in computer networking and certificates for electrical level 1 to 5 (advanced diploma)\n\no Collaborating with Malaysian Qualifications Agency to allow level 4 students to join university degree (technical and vocational education and training- TVET).\n\n\n\no Completed diploma in training institute\n\no Worked (practical) in training institute for 3 months post-training completion\n\no Degree in IT network\n\no Working in private company under IT networking site as project engineer\n\no Youth\n\n\n\no Studied wiring in training institute\n\no Working in training college as a wiring teacher\n\no Worked with father’s business post SPM (secondary school completion cert)\n\no Youth\n\n\n\no Studied level 1 to level 3 diploma in training institute\n\no Working as technician leader\n\no Attended air conditioner services on wiring course\n\no Youth\n\n\n\no Studied electric level 2 to level 4 in training institute\n\no Worked as assistant teacher in training institute\n\no Working as stock keeper currently\n\no Youth\n\n\n\no Studied level 2 and 3 wiring in training institute\n\no Worked as technician\n\no Studied further, waiting for cert\n\no Started own business on house wiring, air conditioner services.\n\no Youth\n\nConcerning research question 1 on the importance of training in the upliftment of B40 youth talents in line with poverty eradication, findings from the interviews are summarised in Figure 1.12 Upon assigning sentiment codes to the transcriptions using NVivo, the majority of trainees and training providers were found to have attested to training being successful in uplifting B40 youth, thereby implying the importance of training in eradicating poverty through B40 youth upliftment.\n\nAs to research question 2 on the proactive measures and their crucial value in the upliftment of B40 youth to eradicate poverty, six themes were explored and summarised in their respective Tables and/or Figures. Firstly, on challenges faced in B40 youth training and action plans. Figure 2 shows that approval, employment, teacher, study, parents, college, and students are keywords used in explaining the challenges faced in B40 youth training. The initial 137 items with synonyms themes that emerged were reduced to 111 items after the removal of non-thematic words. Policymakers believed that tracking employment of the B40 youth after the approval of the training programmes for training providers would be particularly challenging given that the B40 youth tend to leave their jobs within one or two weeks and are very much into business opportunities. The training providers find it challenging to obtain the students’ focus for around eight hours a day while facing complaints from parents about their children being back home late at night. However, they believe that a close relationship with the students, close monitoring and constant updates to parents tend to keep these issues at bay. Meanwhile, trainees find it difficult to understand lessons taught by their teachers and would be required to google further explanations because their tutor pushes them to do so. They also face challenges from their parents not in favour of continuing studies or undergoing training because it would take up time that could be used to earn income at random jobs. Secondly, on interests of the B40 youth group. Figure 3 highlights certain themes that emerge including learning, business, wiring works, hands-on project, teaching, and studying. The initial 117 items with synonyms themes that emerged were reduced to 91 items post-removal non-thematic words. Third, regarding types of training wanted or needed by the B40 youth group (refer to Table 4). Fourth, measures to identify and pool B40 youth participants for training (refer to Table 5). Fifth, the emphasis in governance framework on B40 youth (refer to Table 6). Sixth, strategic perspectives on strategic plans to maximise benefit and minimise challenges of B40 youth training programmes for employment, entrepreneurship, reskilling and upskilling (refer to Table 7).\n\n\n\no Professionalise ordinary jobs like tow truck\n\no Soft skills\n\n\n\no Positive thinking and attitude\n\no Self-motivation\n\no Self-improvement\n\n\n\no Customer relationship\n\n\n\no Detailed wiring courses\n\n\n\no Set requirements\n\no Household income group less than RM3,800 based on guideline set by nation\n\no Training provider find participants\n\no Policy makers request documents like ‘bantuan prihatin nasional’ (scheme for B40 household groups) before approval of training for those participants\n\n\n\no Collaborate with school counsellors\n\no Promote in social media\n\no Collaboration with technical colleges (TVET)\n\n\n\no Identify location, community, select the participants\n\no Do background check in their houses\n\no Household income less than RM3,500\n\n\n\no Collaborate with school counsellors\n\no Promote in social media\n\no Collaboration with technical colleges (TVET)\n\nCOVID = coronavirus disease 2019.\n\n\n\no There is no governance framework specifically targeted at the b40 group.\n\no Training programmes are planned based on prospective outcome in line with government aspirations only when funding is received.\n\n\n\no There is no governance framework specifically targeted at the B40 group.\n\no B40 development funds can be utilised when proposed outcome from training provider is approved.\n\no Future plans to be aimed at B40 development.\n\nCOVID-19 = coronavirus disease 2019.\n\n\n\no Policies and strategic initiatives are driven by government aspirations.\n\no Ongoing discussion on future policies to be targeted at certain groups like B40.\n\no B40 trainings under other ministries.\n\n\n\no Focus more on employment opportunities for anyone, not just B40 as many have lost jobs in times of COVID-19.\n\no Future ready employment post COVID-19.\n\n\nDiscussion and conclusion\n\nFollowing the research questions and findings reported, this study makes the following propositions:\n\n1) Training is the key to uplifting the B40 youth and eradicate poverty.\n\n2) Proactive measures are imperative in the success of B40 youth training towards poverty eradication.\n\nAlthough government aspirations under the shared prosperity vision 2030 have been set to uplift the B40 group, in practice, government training funders are not being guided by a specific framework for B40 youth development. Ministries in charge of B40 training need to work in collaboration with the funder, policymakers, and training providers to better attract the interest of the B40 youth and overcome challenges faced in their training. Figure 4 outlines a framework proposed by the researchers in which every stakeholder needs to come together to uplift B40 youth while considering their interests and the challenges that arise from the training journey. The findings of the study are congruent with the inclusive talent development practices that have been highlighted in previous studies.8,10 The researchers conclude that through proper training and proactive measures via collaboration pathways of multi-stakeholder involvement, the gap between Malaysia’s aspirations and its actual practice on the ground can be closed. The training activities should also involve digital technology skills to keep abreast with the demands in this IR4.0 era.\n\nThe study contributes to the existing literature and practitioners by highlighting the current gap in Malaysia’s aspirations of eradicating poverty in their shared prosperity vision 2030 versus actual organisational practice. Thus, the study suggests that stakeholders come up with proactive strategies to ensure that the right trainees are matched with the right training providers and government policies. A linkage between government policies and industry requirements needs to be established as opposed to the present discontinuity. A structured training needs analysis plan should be put in place through collaborations between industries and governments. However, organisations should be empowered to make decisions instead of constant government reliance to ensure continuous professional development for all within the organisation is embraced. Moreover, B40 individuals commonly found in lower-level positions can be pooled into the career pathway towards a shift into M40. However, the unavailability of statistical representation disables the generalisability of this study’s findings. The qualitative nature of the study is subject to difficulty in causality investigation. Self-reported data are also subject to biases in subjective measures and social desirability.\n\n\nData availability\n\nFigshare: Interview transcript with multi-stakeholder on training in Malaysia for poverty eradication. https://doi.org/10.6084/m9.figshare.16384770.12\n\nThis project contains the underlying data:\n\n• Compiled transcripts.pdf. (This file consists transcription of interview recordings conducted with Malaysia’s multi-stakeholder group including policy makers, trainers, and trainees to gauge proactive measures to eradicate poverty in Malaysia via training.)\n\nFigshare: Interview guide for proactive measures to eradicate poverty in Malaysia in IR4.0 Era: A shared prosperity vision. https://doi.org/10.6084/m9.figshare.16735426.13\n\nThis project contains the underlying data:\n\n• Interview guide.pdf. (This file consists guide used during online semi-structured interviews.)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe would like to express our thanks and appreciation to the Ministry of Higher Education Malaysia for granting us a research grant under the Fundamental Research Grant Scheme (FRGS/1/2019/SS03/UNIM/02/1) to undertake this research and to the respective proofreaders.\n\n\nReferences\n\nPercetakan Nasional Malaysia Berhad: Shared prosperity vision 2030: Restructuring the priorities of Malaysia’s development. [accessed 20 December 2020]. Reference Source\n\nL’Abate L, editors. Paradigms in theory construction. New York:Springer;2012. [accessed 5 May 2021]. Publisher Full Text\n\nHaynes K:Reflexivity in qualitative research.Symon G, Cassell C, editors. Qualitative Organizational Research: Core methods and current challenges. London:Sage;2012; p.72–89. Publisher Full Text\n\nSekaran U, Bougie R: Research methods for business: A skill building approach. West Sussex, United Kingdom:Wiley;7th ed.2016.\n\nCreswell J: Research design: Qualitative, quantitative, and mixed methods approaches. Thousand Oaks, California:Sage;4th ed.2014.\n\nClark VLP, Creswell JW: Understanding research: A consumer’s guide. Upper Saddle River, New Jersey:Pearson Education;2nd ed.2015.\n\nLincoln YS, Guba EG: But is it rigorous? Trustworthiness and authenticity in naturalistic evaluation. N. Dir. Eval. 1986; 30: 73–84.\n\nGolubovskaya M, Solnet D, Robinson RNS: Recalibrating talent management for hospitality: a youth development perspective. Int. J. Contemp. Hosp. Manag. 2019; 31(10): 4105–4125. Publisher Full Text\n\nEconomic Planning Unit: Twelfth Malaysian plan. 2019. [accessed 20 December 2020].Reference Source\n\nBolander P, Werr A, Asplund K: The practice of talent management: a framework and typology. Pers. Rev. 2017; 46(8): 1523–1551. Publisher Full Text\n\nEconomic Planning Unit: Eleventh Malaysia Plan 2016-2020 Anchoring growth on people. 2015. [accessed 20 December 2020].Publisher Full Text\n\nDarmalinggam D: Interview transcript with multi-stakeholder on training in Malaysia for poverty eradication. figshare. Dataset. 2021. Publisher Full Text\n\nDarmalinggam D: Interview guide for proactive measures to eradicate poverty in Malaysia in IR4.0 Era: A shared prosperity vision. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "98146",
"date": "30 Nov 2021",
"name": "Lew Tek-Yew",
"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 article addresses a very important topic of ensuring that training provided by the trainers based on funding from the government has met the objectives of alleviating the poverty level of the B40 youth in Malaysia. The qualitative method used is appropriate for exploratory study. Conclusions are based on the results of the study.\n\nThe authors need to cite the latest literature published in 2020 and 2021 to justify the relationship between training and poverty eradication.\nThe discussion and conclusion section needs to be elaborated to provide the answers to each of the research questions especially on the issue of ‘To what extent: - This study aims to explore the rationale of government intervention in managing B40 youth talent via training in this IR4.0 era. The following research questions guide the study. Research question 1: To what extent is training important in uplifting the B40 youth in line with poverty eradication? Research question 2: What are the proactive measures and to what extent are they crucial to the success of B40 youth training towards poverty eradication?\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": "7588",
"date": "07 Jan 2022",
"name": "Darshana Darmalinggam",
"role": "Author Response",
"response": "Dear respected reviewer, We thank you for a chance to improve our paper. We have compiled the suggestions and comments as per your call, and have addressed the concerns based on your excellent suggestion as follows:- It is a new area of research. As such, no direct citations can be found in 2020-2021. The discussion and conclusion section has now been elaborated to provide answers to each of the research questions especially on the issue of 'To what extent training is important in uplifting B40 youth in line with poverty eradication?' and 'What are the proactive measures and to what extent are they crucial to the success of B40 youth training towards poverty eradication?' Our deepest gratitude to all the Respected Editors and Reviewers for your valuable time taken to scrutinise the content of this paper. We have attempted our very best to improve the quality of this paper. Thank you so much."
}
]
},
{
"id": "98149",
"date": "13 Dec 2021",
"name": "Magda Hewitt",
"expertise": [
"Reviewer Expertise Entrepreneurship",
"emerging economies",
"leadership",
"entrepreneurial leaderhsip"
],
"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 purpose of the study is clearly stated. It is relevant by exploring the mismatch (assumption) between strategic government intervention in managing B40 talent in the IR4.0 era. The chosen methodology is well described and thoroughly executed and reported on. Not clear what is meant by ''very much into business opportunities\". The sample of trainees might be too small to draw any inferences and the needs of the type of training required by them, reflect personal needs. It would be interesting to know how this relates to national training needs. Interesting findings are the training hours and learning material content. This needs more interrogation. The challenges faced by the B40 group are insightful and their reality should be considered when thinking about the study suggestions. I missed a brief overview of 4IR.0 context within this study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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/10-1094
|
https://f1000research.com/articles/11-11/v1
|
06 Jan 22
|
{
"type": "Research Article",
"title": "Knowledge, attitudes and perceptions about HIV self-testing amongst college students in Namibia",
"authors": [
"Malizgani Mhango",
"Vuyiseka Dubula-Majola",
"Leon-Say Mudadi",
"Malizgani Mhango",
"Leon-Say Mudadi"
],
"abstract": "Background: In 2019, the Namibian Ministry of Health introduced HIV self-testing (HIVST) as an additional strategy to increase uptake of HIV self-testing in traditionally hard-to-reach subpopulations, such as young adults and males. It is unclear how the utilisation of HIV self-testing iw optimised in young adults. The study objective is understanding knowledge, attitudes, and perception levels amongst college-going young adults in Namibia. Methods: This quantitative study utilised a sample of 97 young college students who received a pre-test structured questionnaire. One sample t-test was used to analyse the average score from the Likert scale. A cut-off p-value of 0.05 to determine statistical significance of variables was used. Logistic regression computation was used to identify independent variables significantly associated with the dependent variable. A univariate analysis was done on awareness and acceptability with statistical significance of p<0.05 to obtain preliminary insights into the association between independent and dependent variables. The net effect variables are assessed using multivariate analysis using STATA 13.1, taking into account confounding factors. Results: Out of the 97 participants, only 23.7% knew about HIV self-testing. The logistic regression had a significant association with awareness of HIV self-testing (p≤0.05): on condom use during a first sexual encounter; being with a single sexual partner in the last 12 months; not having a sexually transmitted infection. The univariate analysis revealed an association with the acceptability of HIV self-testing from females; those who live in urban settlements; having not had sexually transmitted infection in the last twelve months. Moreover, findings reveal there are low levels of awareness, yet participants had positive attitudes and levels of acceptability to HIV self-testing. Conclusion: This study shows promise if awareness through health education and promotion about HIV self-testing can be increased. This can form part of scaling up HIV testing in Namibia.",
"keywords": [
"HIV self-testing",
"young adults",
"Namibia"
],
"content": "Introduction\n\nThe introduction of Highly Active Antiretroviral Therapy (HAART) in the mid-1990s, has been applauded for its significant reduction of AIDS-related morbidity and mortality (Iloeje et al., 2005). Administration of HAART brought about a tremendous and profound reduction in the rate of immunodeficiency-related opportunistic infections (Iloeje et al., 2005). As well as, the most important stage in the initiation of an HIV positive individual into the care and treatment cascade remains a conclusive HIV diagnostic test (Omondi, Mbogo and Luboobi, 2018). The Joint United Nations Programme on HIV/AIDS (UNAIDS) targets to have reached at least 73% viral suppression in people living with HIV/AIDS (PLWH) by the end of the year 2020 which in turn will make it possible to end AIDS by the year 2030 (Celum and Barnabas, 2019). This ambitious goal is only possible if at least 90% of PLWH are diagnosed and linked to care. Previously, facility-based HIV testing has targeted volunteers, who were mostly women. However, with this strategy; a significant number of men and youth are missed, as they are not as forthcoming as women with regards to testing, and therefore, contribute disproportionately to testing gaps (Kumwenda et al., 2019; Dzinamarira et al., 2020).\n\nVarious centers in the Northern region of Namibia offer HIV testing through voluntary counseling and testing (VCT) where individuals initiate testing and the provider-initiated testing counseling (PITC), where HIV testing is offered to clients who would have visited health centers to access medical services (Jong et al., 2013). The World Health Organisation (WHO) introduced PITC as a way of increasing testing and counseling services uptake (Kennedy et al., 2013). With the setting of 90-90-90 vision 2020 by UNAIDS the government of Namibia through the Ministry of Health and Social Services (MoHSS) increased ways to scale up HIV testing services (HTS) all over the country to reach underserved populations such as young adults and men (Indravudh et al., 2019). All these strategies have seen successes in ensuring universal testing. However, despite these efforts, gaps in meeting the UNAIDS 90-90-90 have been identified by the recent Namibia population-based HIV impact assessment (NAMPHIA) which found that 86 % of PLWH in the age group 15-64 years knew their status with 79.6 % of the males and 89.5 % of females (MoHSS, 2018). In Namibia, HTS has been offered through traditional facility-based testing (MoHSS, 2011), which is considered to lack privacy, delays clients whilst waiting in line for their turn, associated with stigma, inconveniences of distance, and total costs involved (Wood, Ballenger and Stekler, 2014). There has been global progress in the promotion of HIV status awareness even though approximately 50% of PLWH do not know their status (UNAIDS, 2019). To attain the first 90 of the UNAIDS vision 2020 90-90-90 target in young adults, urgent and innovative ways of scaling up HTS are needed to improve the epidemic control as a substantive number of these young adults are unaware of their status in East and Southern Africa (UNAIDS, 2019).\n\nThere is a need for urgent action, as only approximately 10% of the young males and 15% of females, are aware of their HIV serostatus in East and Southern Africa. For this action, innovation is needed to increase HIV testing. Extending HTS out of the immovable facilities might be the solution especially in a country like Namibia where 5% of females and 11% of males are reported to have sex before the age of 15 (Gumede and Sibiya, 2018; UNAIDS, 2019). It is of paramount importance that in the process of scaling up HTS the decision for someone to get tested should not compromise their autonomy (Wurm et al., 2019). This is why it is important to acquaint young adults with HIV self-testing (HIVST).\n\nHIV self-screening tests could help in increasing the number of individuals who have been tested and are aware of their HIV status (Dzinamarira and Mashamba-Thompson, 2019). With HIVST, the individual is accorded with convenience and privacy, as testing can be done in the comfort of one’s home residence. It further adds empowering options for care at the same time, offering means of fast-tracking, pre-screening, and triaging out those who have self-tested negative (Dzinamarira, 2019; Dzinamarira et al., 2020). HIVST will therefore help in closing the existing testing gap between women and young adults, as it can scale up HIV testing coverage and frequency. This will allow health systems to focus only on those who would require further assistance concerning counseling, HIV confirmatory testing, and initiation into the treatment and care cascade. Generally, studies have shown knowledge and acceptance of, and positive attitudes towards HIVST in key populations (Harichund and Moshabela, 2018; Tun et al., 2018; Dzinamarira, Pierre and Rujeni, 2019; Hatzold et al., 2019).\n\nBehaviour change is difficult and complex as it is based on a comprehensive understanding of the factors that influence the uptake and implementation of specific health behaviours. The theoretical domains framework incorporates a range of factors that influence the extent to which a behaviour change can be enacted, such as knowledge, social influences, and emotions among others (Cane, O’Connor and Michie, 2012). This study is based upon the theoretical domains framework as the ability and urge to self-test is dependent on the knowledge, attitudes, and perceptions of an individual. In November 2018, the MoHSS started allowing and urging the citizens of Namibia to make use of HIVST. However, not everyone is versed with this new strategy so there is a need to explore awareness and acceptance through studying how knowledgeable young adults are about this topic, and what their perceptions of and attitudes towards HIVST are. This will help in identifying gaps in scaling up HIVST among potential young adult self-testers in Namibia.\n\n\nMethods\n\nThe study was conducted at Elite Tutorial College in Ondangwa. Elite Tutorial College is a tertiary institution located in Ondangwa town in the Oshana region, which is in the Northern part of Namibia located 60km from the Angola border.\n\nTo calculate the sample size, Cochran’s formula was used.\n\nWhere:\n\nn is the sample size.\n\nZ is the z-value at the 95% level of significance (1.96).\n\np is the (estimated) proportion of the population with the attribute in question. In this case the attribute was knowledge of HIVST which according to Dzinamarira et al. 2019 is 21%. The proportion of knowledge was used in this case as knowledge precedes acceptability and perceptions.\n\nq is 1-p\n\ne is the desired level of precision; i.e., the margin of error which was set at 0.05 in this study.\n\nUsing Cochran’s formula, a sample size of 255 was calculated. However, the total number of students at Elite college is 1000, and this sample size is more than 5% of the population hence a finite population correction had to be factored in to calculate the final sample size. Therefore, a modification to Cochran’s sample size for small populations was used to calculate the new sample size. The following formula was used:\n\nWhere:\n\nn1 is the new adjusted sample size.\n\nn0 is the initial calculated sample size (255 calculated above).\n\nN is the size of the population.\n\nAfter adjusting for the population size, a new sample size of 203 was calculated. However, due to the covid restrictions prevailing at the time the study was conducted the researchers conveniently restricted the sample size to 106 after considering school attendance patterns. Only 96 students finally took part in the study. This still represents more than 5% of the target population hence the results of this study have enough power to infer to the sample population.\n\nThe study used a self-administered structured questionnaire adapted from (Gumede and Sibiya, 2018; Dzinamarira et al., 2020). The questionnaire comprised of 65 questions and used the language of instruction in the College, which is English. The study was approved by the Stellenbosch University Research Ethics Committee (REC): Social, Behavioural and Education Research (SBER) under protocol number HIV-2020-18539. Written informed consent for participation and for publication of the participants’ details was obtained from all participants.\n\nFor this survey, we included four main sections to assess their socio-demographic characteristics, their sexual health, and their health-seeking behaviour, knowledge about HIVST, attitudes, and perceptions towards HIVST and HIV positive status disclosure. We validated the questionnaire through a pilot study at Credential College with a sample of 10 students. The comments from the respondents in the pilot project were used to amend some of the questions in the questionnaire.\n\nThe awareness of and perceived acceptability of HIVST among young adults was assessed in this study.\n\nAwareness of HIVST\n\n“Do you know what HIVST is?” was used to assess the awareness of participants to HIVST; a binary response was captured as either a yes, which was categorised as (Aware), or no, which was categorised as (Unaware)\n\nAcceptability of HIVST\n\n“I would prefer to do an HIV self-test and read the results myself” was used to assess the acceptability of HIVST. The responses for strongly agree and agree were categorized as (Accept) and for neutral, disagree, and strongly disagree were characterized as (Do not accept) to allow for further analysis.\n\nThe researcher collected the questionnaires at the end of each day. Completed questionnaires were stored in a locked file cabinet and only the researcher had access. The data collation and extrapolation from questionnaires was done using Microsoft Excel spreadsheets. Categorical data was checked, for out-of-range and missing values by employing the use of cross-tabulations and frequency tables. Normality tests for continuous data were done using the Shapiro-Wilk test. Frequencies and percentages were used to report categorical variables. Means and standard deviations were used to report normally distributed continuous variables. Median and interquartile ranges were used to report variables that are not normally distributed. A one-sample t-test was used to analyse the average score of results from the Likert scale. A cut-off p-value of 0.05 was used to determine if variables were statistically significant. Univariate logistic regression analysis was carried out to obtain a preliminary insight into the unconditional association of each independent variable and dependent variable. Multivariate logistic regression analysis was employed to assess the net effect of each independent variable on the dependent variable controlling for all other confounding variables. A higher cut-off p-value of 0.25 was used for inclusion in the multivariate model so as not to miss out on vital variables. However, significance in the final model was set at p ≤ 0.05. The overall fitness of the model to the data was tested using the Hosmer and Lemeshow goodness of fit tests and Odds ratios at 95% CI were employed to estimate the effects. Analysis was done using STATA software version 13.1 (Stata, RRID:SCR_012763). A similar analysis was also done using R version 4.1.1 (R Core Team 2021) with no differences in the outputs from the two software. Thus, R can be used as an alternative to STATA and vice versa.\n\n\nResults\n\nA total of 97 participants took part in this survey with a mean (SD) age of 20.8 (±1.85) years. The majority of participants were females (67 [69.1%]). The majority of respondents identified themselves sexually as heterosexuals (79 [81.44%]). The major source of income amongst respondents was parents (71.13%). Table 1 presents more information on the demographic details of participants.\n\nThe mean age for the first sexual encounter is 17.21 (±2.11) years. This is similar to the average age found in a study done among medical students in the Kilimanjaro region in Tanzania. This Tanzanian study revealed that the average age for sexual debut was 19 (Vara et al., 2020) and the majority of respondents (73.2%) reported using a condom on the first sexual encounter which corroborates with a study by Dzinamarira and colleagues showing 75 % of the participants using a condom on their first sexual encounter (Dzinamarira et al., 2020). Consistency of condom use is confirmed by 49.5% of the respondents, while 7.2% reported that they never use condoms during sex. The majority of respondents (67.01%) confirmed having only one sexual partner. About 18% of the respondents reported having contracted an STI within the previous 12 months. Approximately 10% reported not using a condom in the last 12 months. Of the 30 men, 43% reported being circumcised. More information about health-seeking behaviour and sexual health is presented in Table 2 below.\n\nKnowledge of HIVST was very limited in this sample of respondents with the majority of respondents (76.29%) confirming that they do not know what HIVST is all about. The same proportion of respondents reported that they had never heard about HIVST, while a slightly higher proportion (79.38%) said they had never read about HIVST. Despite this, more than 90% of the respondents confirmed that they had never used an HIVST kit, and at least more than half of them (51.04%) were aware that HIVST kits are legally allowed to be used in Namibia. Most participants were aware of the existence of HIVST kits in private pharmacies (78.35%), while only 44.33% were aware that HIV test kits were available on the internet platforms. The majority of respondents indicated that HIVST is done using blood (89.69%) with less indicating that saliva can also be used as a sample for HIVST (22.68%). Table 3 is a summary of the findings on the knowledge of HIVST by respondents.\n\nIn cross-tabulations, there is no existence of a significant difference in knowledge of HIV self-testing between males and females (p > 0.05) in all the attributes except for the need to have a retest after 3 months when the test is negative (p = 0.009), as shown in Figure 1 below. A higher proportion of females (86.57%) were more knowledgeable compared to their male counterparts in this attribute.\n\nOverall, respondents had a positive attitude towards HIVST. About 84% of the participants agreed/strongly agreed that HIV self-testing is a good idea while 80.41% agreed/strongly agreed that they can self-test at home using the HIV self-test kit. In addition, 82.47% of the respondents confirmed that they are happy to do the self-test with their sexual partner (Strongly agree – 55.67%, Agree – 26.8%). If the test result is positive, 87.63% of the respondents agreed/strongly agreed that they would seek help from a health facility. In addition, 92.78% of the respondents agreed that it is vital to get counseling and health advice after a positive HIV test result. Table 4 summarises the attitude of respondents towards HIVST and linkage to care.\n\nPerceptions on HIVST and disclosing HIV-positive status were largely positive. About 82% of the respondents perceived HIV self-testing as a faster strategy of ensuring that more individuals become aware of their HIV status (Strongly agree – 50.52%, Agree – 31.96%). This would enable screening of those who test positive and allow health professionals to triage them quickly to access treatment early before the disease progresses, as attested to by 71.13% of the respondents (Strongly agree – 38.14%, Agree – 32.99%). On disclosing one’s HIV status, the majority of respondents (78.35%) said HIV positive status should be a secret and this agreement was strong (Mean = 1.86, SD= 1.03, t (96) = -10.9, p = 0.00). Furthermore, 65.98% agreed that those who test positive should only disclose their status to partners and this agreement was strong (Mean=2.25, SD=1.27, t (96) = -5.8, p = 0.00). There was no significant agreement or disagreement with respect to HIV positive people disclosing their status to significant others (Mean = 3.06, SD = 1.32, t (96) = 0.46, p = 0.65). A significant proportion of respondents (59.8%) disagreed with the notion that HIV positive people should talk openly about their HIV status (Mean = 3.54, SD = 1.35, t (96) = 3.99, p = 0.001). Table 5 summarises the perceptions towards HIVST and HIV positive status disclosure.\n\nUnivariate analysis (Awareness)\n\nIn the univariate analysis, a year increase in age was associated with a two percent increase in awareness of HIVST [OR = 1.02; 95%CI (0.79; 1.31)]. Individuals who never used a condom during their first sexual encounter were 5% less likely to be aware of HIVST as compared to those who used a condom on their sexual debut [OR = 0.95; 95% CI (0.33; 2.76)]. Having one sexual partner in the last 12 months was associated with a 53% increase in HIVST awareness compared to those individuals with more than one sexual partner within the same 12-month period [OR = 1.53, 95% CI (0.54; 4.37). Individuals who had never suffered from an STI within the last 12 months were 55% more likely to be aware of HIVST in comparison to those who had suffered from an STI within the same period [OR = 1.55, 95% CI (0.40; 5.97)]. Unfortunately, none of these associations was statistically significant at the 95% level of significance (p ≤ 0.05). In addition, no variables were significant for inclusion into the multivariate analysis. Univariate analysis findings with awareness as the dependent variable are presented in Table 6.\n\nUnivariate analysis (Acceptability)\n\nAn increase in age by a year was associated with a five percent increase in HIVST acceptability [OR = 1.05; 95% CI = (0.83; 1.32)], with women being 36% more likely to accept HIVST compared to men [OR = 1.36; 95% CI = (0.55; 3.37)]. Individuals residing in urban areas were two percent more likely to accept HIVST compared to those residing in rural areas [OR = 1.02; 95% CI = (0.40; 2.57)], while those residing in informal settlements were 95% more likely to accept HIVST compared to those in rural areas [OR = 1.95; 95% CI = (0.20; 18.61)]. However, at the 95 % level of significance (p≤0.05); none of these findings were statistically significant. The odds of accepting HIVST were 2.97 higher among those who had never suffered an STI in the last 12 months as compared to those who had suffered from an STI within the same period [OR = 2.97; 95% CI = (1.02; 8.66)] and this was statistically significant (p = 0.047). Results from the univariate analysis for acceptability are presented in Table 7.\n\nOnly two variables (suffered an STI in the last 12 months and gifts for sex) were eligible for inclusion into the multivariate model using a cut-off p-value of 0.25. However, in the multivariate model, none of the two was significant, thus the model was dropped.\n\n\nDiscussion\n\nThe study’s main aim was to explore how knowledgeable young adults in Ondangwa are to HIVST, their attitudes, perceptions, and acceptability of home-based approaches to HIV testing. This study brought up vital findings; firstly, young adults lack knowledge on HIVST as only 23% revealed knowing about HIVST; secondly, this study showed a positive attitude towards HIVST as they agreed that it was a good idea. The participants showed positive perceptions about HIVST offering privacy, allowing positive people to get treatment before they get sicker but issues of regulation, suicide, and abuse by family members and employers. Demographics revealed that the study predominantly consisted of females with 69% of the participants being female and 31% being male. Of those who took part in this study, 89% spoke Oshiwambo with few representations from other ethnic groups. A recent population and housing census conducted by the Namibian Statistics Agency, found that the Oshana region is home to approximately 91% Oshiwambo speaking (NSA, 2017) which is in line with the findings of this present study.\n\nThe study found out that only 23% were aware of HIVST and had heard about it whilst 68% of the participants found it acceptable. Of importance to this study is the focus by the republic of Namibia in the 2017/2018 – 2021/2022 HIV and AIDS strategic framework. The HTS section of the AIDS strategic framework seeks to improve HTS uptake among young adolescents (MoHSS, 2017) as a vital step in meeting the 90-90-90 UNAIDS and ending HIV/AIDS by 2030. Studies have reported that HIVST offers the capacity to close the testing gap (Freeman et al., 2018; UNAIDS, 2019). In this study, the reports about condom usage during the first sexual encounter, late sex debut (sex after 18 years), knowledge of HIVST, and positive attitude towards HIVST and HIV risk perception were found to be factors associated with HIVST awareness. The present study further found that health-seeking behaviour, knowledge of HIVST, and positive attitude towards HIVST to be factors associated with acceptability of HIVST. The results from the present study corroborate previous calls to find solutions to poor sexual reproductive health-seeking behaviour by young adults and men (Ekouevi et al., 2020). Due to lack of knowledge, use was also minimal as only 9% reported having self-tested before, with 76 % reporting they knew that HIVST kits existed in private pharmacies. This corroborates with what Greacan et al. recommended in their study in 2016 that free HIVST kits be made available in medical centers and other public institutions (Greacen et al., 2016).\n\nApproximately 60% of the participants in this study preferred to test alone and this has been evidenced as well in a study by Young and colleagues in 2014 (Young et al., 2014). The participants unanimously (87.6%) agreed that they would seek medical help with a positive HIV test result. Previous studies (Kalibala et al., 2014; van Rooyen et al., 2015; Gumede and Sibiya, 2018) agree with these results. Despite participants indicating positively that they would follow up with health professionals after a positive HIV self-test result, Peate (2015) raised concerns about the lack of linkage to care of HIVST citing that, contacting a health professional is an individual responsibility (Peate, 2015). Concerns about confidentiality in HIVST were raised by 78% of the participants agreeing on secrecy regarding the HIV positive test and 55% disagreeing to disclose a HIVST positive result to their sexual partners; this corroborates with studies by Dzinamarira and colleagues and that by Gumede and colleague (Dzinamarira et al., 2020; Gumede and Sibiya, 2018).\n\nDespite participants agreeing to HIVST as part of the HIV/AIDS epidemic control, 67.7 % of participants fear incorrect readings and poor interpretation of the test results, which may lead to either false positives or false negatives. Furthermore, 64.9 % agreed that testing instructions could be wrongly read and interpreted. These fears have also been of concern in past studies (Ng et al., 2012; Choko et al., 2015; Martínez Pérez et al., 2016; Sarkar et al., 2016; Gumede and Sibiya, 2018). Regulation of HIVST kits sale has not yet been enacted in Namibia both online and in pharmacies and in this study, 56.6 percent agreed that if not regulated by the government, chances of illegal HIVST kits flooding the streets are high. This drawback has been of concern in past studies (Koutentakis et al., 2016; Williams et al., 2017; Gumede and Sibiya, 2018). The findings of this study revealed low awareness of HIVST at 23 percent and high acceptability of 68 percent among young adults attending Elite tutorial college in Ondangwa. Previous studies done in different subpopulations revealed similar patterns; for example, a study in Kigali Rwanda among men by Dzinamarira and colleagues revealed an awareness of 21 % and acceptability as high as 74 % (Dzinamarira, 2020); whilst another study among bisexual men in Australia revealed that 41.9 % were aware of HIVST (Dean et al., 2019). A South African study done in the district of eThekwini in KwaZulu Natal showed higher levels of awareness at 69.9 % (Gumede and Sibiya, 2018). The similarity of the study in eThekwini to this present study is that they both had an almost similar representation of (males 30.1 % females 68.8), and (males, 30.9 % females 67.7 %) respectively. Other studies that were done in Peru and Brazil also revealed awareness at high levels of 97 % among men (Volk et al., 2016). In addition, the low levels of awareness may be due to HIVST being a new intervention that many people are not aware of and it is still in its inception stages.\n\nThe findings of this study found HIVST acceptability at 68.8%. Acceptability slightly lower than this of 56.2% was found among Australian MSM (men who have sex with men) and bisexual men (Dean et al., 2019). In a study among Chinese MSM 43.8 % found HIVST to be acceptable (Wong et al, 2015). Attributes to variations in acceptability also vary according to differences in the sampled populations. In both Dean et al. and Wong et al., the sampled populations were MSM (Dean et al., 2019; Wong et al, 2015). A study among 3662 South African students showed acceptability of 75% with around 43.4% of the sample being males (Mpata Mokgatle and Madiba, 2017). High acceptability of this magnitude was also found out in a Kenyan study (Kalibala et al., 2014). Results of this survey corroborate findings from a systematic review carried out by Krause and colleagues in 2013 (Krause et al., 2013). The findings from this study are also in tandem with findings from literature reviews by Figueroa and colleagues (Figueroa et al., 2018) and Pant Pai and colleagues (Pant Pai et al., 2013). Acceptability of HIVST in SSA has been found out to range from 22% to 94% with a biased pattern where men benefit more than women from HIVST interventions (Kurth et al., 2016; Maheswaran et al., 2016). In comparison, studies that have men only reported high acceptability rates of around 70 to 94% whilst those that include women as the present study ferry around 22 to 64% (Dyk, 2013; Kurth et al., 2016; Gumede and Sibiya, 2018; Vara et al., 2020). The highlights of this study are that key factors such as knowledge of HIVST and health-seeking behaviour influence the acceptability of HIVST. This is similar to findings from another study by Izizag and colleagues (Izizag et al., 2018).\n\nThe Namibian government should implement a programme that increases awareness of HIVST in universities and colleges as well as in secondary schools. We recommend designing innovative policies that ensure HIVST is offered in a more youth appealing, user-friendly, and readily available to those who never took HTS for whatever reasons (Wong et al., 2014; Van Rooyen et al., 2015).\n\n\nConclusion\n\nThe findings from this current study revealed low levels of HIVST knowledge but the young adults in this study showed high acceptability of HIVST. These findings accentuate the importance of advancing awareness programmes for HIVST as an alternative strategy of scaling uptake of HTS among young adults in Namibia.\n\n\nData availability\n\nThe data that support the findings of this study cannot be made openly available due to security risks. The data will be made available to researchers upon reasonable request by emailing the corresponding author.",
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PLoS One. 2016; 11(3): p. e0152567. Publisher Full Text Edited by G. Prestage.\n\nGumede SD, Sibiya MN: Health care users’ knowledge, attitudes and perceptions of HIV self-testing at selected gateway clinics at ethekwini district, kwazulu-natal province, South Africa. SAHARA J-J SOC ASP. 2018; 15(1): 103–109. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarichund C, Moshabela M: Acceptability of HIV Self-Testing in Sub-Saharan Africa: Scoping Study. AIDS Behav. Springer New York LLC. 2018; 22: pp. 560–568.Publisher Full Text\n\nHatzold K, et al.: HIV self-testing: breaking the barriers to uptake of testing among men and adolescents in sub-Saharan Africa, experiences from STAR demonstration projects in Malawi, Zambia and Zimbabwe.2019. Publisher Full Text\n\nIloeje UH, et al.: Protease inhibitor exposure and increased risk of cardiovascular disease in HIV-infected patients. HIV Med. 2005; 6(1): 37–44. PubMed Abstract | Publisher Full Text\n\nIndravudh PP, et al.: Community-led delivery of HIV self-testing to improve HIV testing, ART initiation and broader social outcomes in rural Malawi: Study protocol for a cluster-randomised trial. BMC Infect. Dis. 2019; 19(1): 814. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIzizag BB, et al.: Factors associated with acceptability of HIV self-testing (HIVST) among university students in a Peri-Urban area of the Democratic Republic of Congo (DRC). Pan Afr. Med. J. 2018; 31: 1–9. Publisher Full Text\n\nJong E, et al.: Consensus statement: Management of drug-induced liver injury in HIV-positive patients treated for TB. South Afr J HIV Med. 2013; 14(3): 113–119. Publisher Full Text\n\nKalibala S, et al.: Factors associated with acceptability of HIV self-testing among health care workers in Kenya. AIDS Behav. 2014; 18(SUPPL. 4): 405–414. Publisher Full Text\n\nKoutentakis K, et al.: Knowledge and use of unauthorized HIV self-test kits among men who have sex with men in Spain, following approval of an over-the-counter self-test in the U.S: A cross-sectional study. BMC Public Health. 2016; 16(1): 532. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKrause J, et al.: Acceptability of HIV self-testing: A systematic literature review. BMC Public Health. 2013; 13(1): 735. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumwenda MK, et al.: Exploring social harms during distribution of HIV self-testing kits using mixed-methods approaches in Malawi. J. Int. AIDS Soc. 2019; 22(S1): e25251. Publisher Full Text\n\nKurth AE, et al.: Accuracy and Acceptability of Oral Fluid HIV Self-Testing in a General Adult Population in Kenya. AIDS Behav. 2016; 20(4): 870–879. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaheswaran H, et al.: Cost and quality of life analysis of HIV self-testing and facility-based HIV testing and counselling in Blantyre, Malawi. BMC Med. 2016; 14(1): 34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMartínez Pérez G, et al.: Supervised oral HIV self-testing is accurate in rural KwaZulu-Natal, South Africa. Tropical Med. Int. Health. 2016; 21(6): 759–767. PubMed Abstract | Publisher Full Text\n\nMinistry of Health and Social Services: Namibia Population-based HIV Impact Assessment (NAMPHIA) 2017 NAMPHIA 2017 Collaborating Institutions The PHIA Project. Windhoek: 2018\n\nMinistry of Health and Social Services (MoHSS): Ministry of Health and Social Services National Guidelines for HIV Counselling and Testing in Namibia. 2011.\n\nMpata Mokgatle M, Madiba S: High Acceptability of HIV Self-Testing among Technical Vocational Education and Training College Students in Gauteng and North West Province: What Are the Implications for the Scale Up in South Africa?.2017. Publisher Full Text\n\nNg OT, et al.: Accuracy and User-Acceptability of HIV Self-Testing Using an Oral Fluid-Based HIV Rapid Test. PLOS ONE. 2012; 7(9): e45168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOmondi EO, Mbogo RW, Luboobi LS: Mathematical modelling of the impact of testing, treatment and control of HIV transmission in Kenya. Cogent Mathematics & Statistics. 2018; 5: 1475590. Publisher Full Text\n\nPant Pai N, et al.: Supervised and Unsupervised Self-Testing for HIV in High- and Low-Risk Populations: A Systematic Review. PLoS Med. 2013; 10: e1001414. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPeate I: HIV self-testing kits. Surgical nurse. 2015; 24: 663. PubMed Abstract | Publisher Full Text\n\nR Core Team: R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. Reference Source\n\nSarkar A, et al.: Feasibility of supervised self-testing using an oral fluid-based HIV rapid testing method: A cross-sectional, mixed method study among pregnant women in rural India: A. J. Int. AIDS Soc. 2016; 19(1) PubMed Abstract | Publisher Full Text | Free Full Text\n\nTun W, et al.: Uptake of HIV self-testing and linkage to treatment among men who have sex with men (MSM) in Nigeria: A pilot programme using key opinion leaders to reach MSM.2018. Publisher Full Text\n\nUnited Nations Joint Programme on HIV/AIDS (UNAIDS): UNAIDS Data 2019.2019. p. 476. Reference Source\n\nvan Rooyen H , et al.: What are the constraints and opportunities for HIVST scale-up in Africa? Evidence from Kenya, Malawi and South Africa. J. Int. AIDS Soc. 2015; 18(1): 19445. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVara PA, et al.: Level of knowledge, acceptability, and willingness to use oral fluid HIV self-testing among medical students in Kilimanjaro region, Tanzania: A descriptive cross-sectional study. AIDS Res. Ther. 2020; 17(1): 56. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVolk JE, et al.: Acceptability and feasibility of HIV self-testing among men who have sex with men in Peru and Brazil. Int. J. STD AIDS. 2016; 27(7): 531–536. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilliams OD, et al.: Implications of the on-line market for regulation and uptake of HIV self-testing in Australia. AIDS Care. 2017; 29(1): 112–117. PubMed Abstract | Publisher Full Text\n\nWood BR, Ballenger C, Stekler JD: Arguments for and against HIV self-testing. HIV/AIDS (Auckl). 2014; 6: 117–126. Publisher Full Text\n\nWurm M, et al.: Zugangsschwellen zu HIV-Test-Angeboten – Eine systematische Literaturanalyse. Das Gesundheitswesen. 2019; 81(03): e43–e57. Publisher Full Text\n\nYoung SD, et al.: Acceptability of using electronic vending machines to deliver oral rapid HIV self-testing kits: A qualitative study. PLoS One. 2014; 9(7): e103790. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "118857",
"date": "19 Apr 2022",
"name": "Tracey Naledi",
"expertise": [
"Reviewer Expertise Public Health Medicine special interest in HIV",
"Adolescent Health",
"Health Equity"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is important research investigating an important issue to advance HIV prevention, early diagnosis, and early treatment specifically for young people and other vulnerable groups.\nMinor comments:\nTypo in Abstract second sentence (iw)\n\nPlease define young adults\n\nPlease provide a reference for “approximately 10% of the young males and 15% of females, are aware of their HIV serostatus in East and Southern Africa”\n\nPlease use SARS-CoV-2 or COVID-19 in full not covid please\n\nPlease include date of research\n\nThis statement is not clear “A higher proportion of females (86.57%) were more knowledgeable compared to their male counterparts in this attribute.”\n\nIt is not clear what the mean values, SD etc. are measuring please clarify “On disclosing one’s HIV status, the majority of respondents (78.35%) said HIV positive status should be a secret and this agreement was strong (Mean = 1.86, SD= 1.03, t (96) = -10.9, p = 0.00). Furthermore, 65.98% agreed that those who test positive should only disclose their status to partners and this agreement was strong (Mean=2.25, SD=1.27, t (96) = -5.8, p = 0.00). There was no significant agreement or disagreement with respect to HIV positive people disclosing their status to significant others (Mean = 3.06, SD = 1.32, t (96) = 0.46,p = 0.65). A significant proportion of respondents (59.8%) disagreed with the notion that HIV positive people should talk openly about their HIV status (Mean = 3.54, SD = 1.35, t (96) = 3.99, p = 0.001).\"\n\nThe results section is for results of the study only – please do not include any commentary or references to other studies that belong in the discussion.\n\nMajor methods issues\nHow comparable to the broader population is this study sample? Only one variable i.e distribution of Oshiwambo speaking people is included.\n\nThe sample size is less than half what was calculated, how did the authors choose the 96 people?\n\nResults must have p values\n\nThe results to be discussed in the discussion must be in the results section and not only in the tables\n\nThe authors have used results that are not statistically significant to make conclusions “ In this study, the reports about condom usage during the first sexual encounter, late sex debut (sex after 18 years), knowledge of HIVST, and positive attitude towards HIVST and HIV risk perception were found to be factors associated with HIVST awareness.” Please be explicit that this is not statistically significant and explain the implications of this.\n\nLimitations of the study must be included especially with the sample size issues raised\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": []
},
{
"id": "128670",
"date": "27 Apr 2022",
"name": "Odette Ky-Zerbo",
"expertise": [
"Reviewer Expertise Public health-Qualitative 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\nIt is an article that provides basic information on the level of knowledge and attitudes about ADVIH by youths. This can be a lever for the introduction of HIVST in Namibia. However, the authors should be more explicit and detailed on some points in the article that were noted in the comments provided. Their statistical analyses and interpretations deserve another opinion.\nComments:\nAbstract section\n“In 2019, the Namibian Ministry of Health introduced HIV self-testing (HIVST) as an additional strategy to increase uptake of HIV self-testing in traditionally hard-to-reach subpopulations, such as young adults and males”: I hope you want to mean “to uptake HIV testing”.\n\nIt is unclear how the utilisation of HIV self-testing is optimised in young adults\n\n“The logistic regression had a significant association with awareness of HIV self-testing (p≤0.05): on condom use during a first sexual encounter; being with a single sexual partner in the last 12 months; not having a sexually transmitted infection. The univariate analysis revealed an association with the acceptability of HIV self-testing from females; those who live in urban settlements; having not had sexually transmitted infection in the last twelve months” is different from the results section where you write “Unfortunately, none of these associations was statistically significant at the 95% level of significance (p ≤ 0.05)”.\nIntroduction section.\n\nThe references related to Highly Active Antiretroviral Therapy impact should be updated, and cited from direct sources. For example, the authors cited Iloeje et al., who have cited other sources.\n\nThe same suggestion about “UNAIDS statement about 73% viral suppression….”. Why did they cite other authors than UNAIDS? https://www.unaids.org/sites/default/files/media_asset/global-AIDS-strategy-2021-2026_en.pdf\n\nJong et al publication is not available\n\n“The World Health Organisation (WHO) introduced PITC as a way of increasing testing and counseling services uptake”. Why didn't the authors cite WHO PITC guidelines directly?\n\nWhile citing Namibia government policy, they mentioned another author. Why?\n\nI suggest changing “UNAIDS vision 2020 90-90-90 target” to the 95-95-95 target.\n\nSome publications could be useful for the authors\n\nFor UNAIDS targets: https://www.unaids.org/sites/default/files/media_asset/global-AIDS-strategy-2021-2026-summary_en.pdf\n\nvan Empel E, De Vlieg RA, Harling G, Marcus ME, Kahn K, Bärnighausen TW, et al. Reaching for the « first 95 »: a cross-country analysis of HIV self-testing in nine countries in sub-Saharan Africa. AIDS. 1\n\nLyons CE, Coly K, Bowring AL, Liestman B, Diouf D, Wong VJ, et al. Use and Acceptability of HIV Self-Testing Among First-Time Testers at Risk for HIV in Senegal. AIDS Behav. 2\n\nMethods section\nWe lack information on the study period, and how many times the authors took to collect data\n\nThe sampling was not described: “Only 96 students finally took part in the study” how have they been selected?\n\nWe need more details to understand how participants expressed their opinions and attitudes in this section to understand the results. For example, more students than those who have ever heard about HIVST reported that they will be able to do HIVST by themselves; or disagree that “HIV self-testing procedure difficult to perform…”; How did they know HIVST and give their opinion?\n\nThe number of participants varied: 96 in the method section and 97 for the results.\n\nIt seems like acceptability is defined as a preference by authors; somebody can accept HIVST but doesn’t prefer it to usual HIV testing services. And this can contribute to underestimating the acceptability percentage in the study. If they agree with that, it must be discussed in the “discussion section”.\n\nAlso, in this section, it’s “perceived awareness” and I agree with that because it’s a self-report. But in the other sections of the article, they write “awareness”. Could they be more rigorous, and also discuss this aspect at the end? Perhaps in a “study limitation “ section?\nResults section\nThe statistics in Table 1 must be checked. For example, the total percentage of reported sexual orientation is over 100%.\n\nIt seems like the sample is insufficient for these quantitative analyses. Also, the authors specified that they “conveniently restricted the sample size to 106”.\n\nThe mean age for the first sexual encounter is 17.21 (±2.11) years. What about males and females? We know that girls are having sex earlier sex than boys. When providing results, give more gender details; data in tables 1-3 could be presented by gender.\n\nCondom use items: In general, the number of participants who were sexually active in a given time period, such as the last 12 months, is sought before exploring sexual behaviors. If participants reported not having had sex in the last 12 months, for example, they should be subtracted before calculating percentages. Could you clarify whether all participants were sexually active during the time period?\n\nAvoid discussing the results by providing information from other authors in the results section. To move to the discussion section:\n\nThis is similar to the average age found in a study done among medical students in the Kilimanjaro region in Tanzania. This Tanzanian study revealed that the average age for sexual debut was 19 (Vara et al., 2020) and the majority of respondents (73.2%) reported using a condom on the first sexual encounter which corroborates with a study by Dzinamarira and colleagues showing 75 % of the participants using a condom on their first sexual encounter (Dzinamarira et al., 2020)\n\nThis result is somewhat unclear “Knowledge of HIVST was very limited in this sample of respondents with the majority of respondents (76.29%) confirming that they do not know what HIVST is all about. The same proportion of respondents reported that they had never heard about HIVST….and at least more than half of them (51.04%) were aware that HIVST kits are legally allowed to be used in Namibia”. Could you give more details or discuss it?\n\n“Retest needed after 3 months if test is negative”. Is it a recommendation from Namibia to retest 3 months later? If so, write it in the introduction section because this is not a WHO recommendation. See page 104,\n\nat https://apps.who.int/iris/rest/bitstreams/1313903/retrieve\n\nI suggest presenting the results in a table, with all items, and not a figure with only gender analysis.\nUnivariate analysis (Awareness); urban residence seems to be statistically associated with good awareness\n\nGifts for sex are not statistically associated with acceptability. The sentence “Only two variables (suffered an STI in the last 12 months and gifts for sex) were eligible for inclusion into the multivariate model…” must be corrected\n\nDiscussion section\nIn the discussion at the end of each paragraph, please draw a conclusion in terms of public health: do you have any hypotheses or recommendations to make regarding these results? The discussion is not simply a comparison of the results with those of other authors.\n\nStudy limitation discussed by the authors: “Demographics revealed that the study predominantly consisted of females with 69% of the participants being female and 31% being male. Of those who took part in this study, 89% spoke Oshiwambo with few representations from other ethnic groups...”. This may be a limitation? I suggest removing this if it is not a limitation of the study.\n\nParagraph 1.\nHIVST is different from home-based testing because it can be used at any place\n\nParagraph 2\n“as a vital step in meeting the 90-90-90 UNAIDS and ending HIV/AIDS by 2030” to check and accurate according to UNAIDS statement; it’s 95-95-95 by 2030. Reference also needed\n\n…”in meeting the 90-90-90 UNAIDS and ending HIV/AIDS by 2030”: could you let us know the reference, please?\n\nI am not very comfortable with this conclusion “ In this study, the reports about condom usage during the first sexual encounter, late sex debut (sex after 18 years), knowledge of HIVST, and positive attitude towards HIVST and HIV risk perception were found to be factors associated with HIVST awareness. The present study further found that health-seeking behaviour, knowledge of HIVST, and positive attitude towards HIVST to be factors associated with acceptability of HIVST\" because the authors seem to assert the opposite in the results section.\n\nParagraphs 1 &2: Some repetitions like “The study found out that only 23% were aware of HIVST and had heard about it whilst 68% of the participants found it acceptable” to be avoided.\n\n“…use was also minimal as only 9% reported having self-tested before, with 76 % reporting they knew that HIVST kits existed in private pharmacies”. Maybe you can suppose that is a financial barrier to access and not a lack of information on HIVST, which is in line with the following sentence and recommend free access to HIVST kits.\n\nParagraph 3. “Concerns about confidentiality in HIVST were raised by 78% of the participants agreeing on secrecy regarding the HIV positive test and 55% disagreeing to disclose a HIVST positive result to their sexual partners;…”. Was this attitude specific to HIVST in the Namibia context? It seems to be a general attitude regarding HIV. What suggestion or recommendation could you do to help to remove this barrier?\n\nParagraph 5. SSA to detail\n\nThe recommendation section could be a part of the conclusion.\n\nA study limitation section needs to be added.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-11
|
https://f1000research.com/articles/9-1335/v1
|
16 Nov 20
|
{
"type": "Study Protocol",
"title": "Assessment of risk perception and risk communication regarding COVID-19 among healthcare providers: An explanatory sequential mixed-method study in Bangladesh",
"authors": [
"Marium Salwa",
"M Atiqul Haque",
"Muhmammad Ibrahim Ibne Towhid",
"Sarmin Sultana",
"Mohammad Tanvir Islam",
"Md Maruf Haque Khan",
"Md Titu Miah",
"Syed Shariful Islam",
"Syed Moniruzzaman",
"M Atiqul Haque",
"Muhmammad Ibrahim Ibne Towhid",
"Sarmin Sultana",
"Mohammad Tanvir Islam",
"Md Maruf Haque Khan",
"Md Titu Miah",
"Syed Shariful Islam",
"Syed Moniruzzaman"
],
"abstract": "Background: Any public health emergency demands adequate risk communication with the vulnerable population along with their optimized perception about the impending risk to ensure proper risk management and crisis control. Hence, this study will be conducted to explore healthcare providers’ perceptions regarding risks of coronavirus disease 2019 (COVID-19), as well as how they are being communicated to about the risk, and how they practice risk reduction measures. Methods: A two-phased explanatory sequential mixed-method study will be conducted among physicians and nurses from randomly selected tertiary healthcare facilities in Dhaka, the capital of Bangladesh. In the first phase, the general pattern and quantifiable measures of risk perception, risk communication, and infection prevention practices will be assessed quantitatively. Multiple linear regression analyses will be performed to explore how much variability of risk perception is predicted by risk communication methods and contents. In the second phase, qualitative data will be collected for in-depth understanding and exploration of participants’ experiences and insights regarding COVID-19 risk through interviews and document reviews. Thematic content analysis of the qualitative data will be done manually. Findings from both quantitative and qualitative phases will then be triangulated to illustrate the research objectives. Discussion: Based on the psychometric dimensions of risk perception and psycho-social theory of the health belief model, perception of COVID-19 risk among healthcare providers will be evaluated in this study. The relationship between risk perception and infection prevention and control practices among healthcare providers will also be investigated. The explanatory sequential design of this study is expected to generate hypotheses on how risk perception is being shaped in a time of uncertainty and thus, will help to build a proper risk communication strategy to minimize risk perception among healthcare providers.",
"keywords": [
"risk perception",
"risk communication",
"infection prevention and control practice",
"healthcare providers",
"COVID-19",
"Bangladesh"
],
"content": "Introduction\n\nThe role of health professionals is crucial during an outbreak such as in the current coronavirus disease 2019 (COVID-19) pandemic to maintain population health and provide assurance in retaining healthcare system order. Hence, a clear understanding of how healthcare providers are being communicated with about the risk and how they perceive the risk is essential for emergency preparedness and crisis management1 during public health emergencies.\n\nWhen risk is the anticipation of a catastrophe, perception applies to the mental processes through which a person deals with the disastrous event2. Studies of risk perception examine the judgments people make when they are asked to characterize and evaluate any hazardous situation3. Empirical studies show that perception and acceptance of risk have their roots embedded in social and cultural factors4 and research evaluating risk perception often offers important pointers concerning the selection of dimensions that need to be focused on for risk management. On the other hand, risk communication is multi-directional communication and engagement with the population at risk, so that they can make informed decisions to protect themselves5. In any health emergency, risk communication is directed to share information essential for saving lives, preserving health, and minimizing harm through changing perception and behaviour5. Communicating risk with healthcare providers is important as it might influence their understanding of the risk, willingness to serve at the frontline and enhance their preventive practices in times of need.\n\nA recent qualitative study in China reported that healthcare providers experienced several challenges while working in COVID-19 wards that include heavy workloads, exhaustion from wearing protective gear, fears of being infected, and a sense of powerlessness while fulfilling their professional responsibilities for patients’ wellbeing6. During the severe acute respiratory syndrome (SARS) epidemic in Japan, a study revealed a high level of risk perception among healthcare providers and hence, emphasized on planning and implementing institutional measures during any health emergency7. Bangladesh reported its first Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) positive case on 8 March 2020, around three months after the first reported case in China. Yet, experiences of Bangladeshi healthcare providers during the COVID-19 pandemic remain mostly unexplored. With a steep rise in new COVID-19 cases in Bangladesh, many healthcare providers have already been infected. Under the circumstances, a clear understanding of different perspectives of disease risk and prevention is needed in order to develop effective prevention strategies8. A detailed understanding of risk perception is also essential for effective risk communication and risk management9. This study has been designed to examine the communication made with healthcare providers and their perceptions regarding the risks related to COVID-19.\n\n1. How do healthcare providers perceive risks related to the ongoing COVID-19 pandemic in Bangladesh?\n\n2. What are the communication channels, influencers, and content used for communicating COVID-19 risk with the healthcare providers in Bangladesh?\n\n3. How do healthcare providers engage in COVID-19 infection prevention and control practices in healthcare settings?\n\n4. How risk perception is being shaped by the nature of risk communication among healthcare providers at the time of the COVID-19 pandemic?\n\n\nMethods\n\nThis will be a two-phased explanatory sequential mixed-method study. According to the study design, a quantitative cross-sectional study will be conducted in the first phase to evaluate the general pattern and quantifiable measures of the research objectives. In the second phase, qualitative data will be collected for in-depth understanding and exploration of participants’ experiences and insights. Data from both quantitative and qualitative phases will then be triangulated to illustrate the answer to each research question.\n\nRegistered physicians and nurses working at different tertiary care hospitals in Dhaka, the capital of Bangladesh, will be invited. More than half of the COVID-19 patients in Bangladesh are concentrated in Dhaka10. Here, some healthcare facilities have been dedicated for the treatment of COVID-19 patients while others are open to all patients. Using a lottery method, six facilities will be selected as study sites from the list of public tertiary healthcare facilities in Dhaka.\n\nFirst phase: Quantitative data collection. The sample size has been calculated by 4pq/L2. Considering the perception of 50% (p), q as 1− p, 5% allowable error (L), 95% confidence interval, and 10% non-response rate, the calculated sample size is 440 participants. Thus, recruiting at least 440 participants will be adequate for this study.\n\nDuring the ongoing COVID-19 pandemic, healthcare providers in tertiary care hospitals in Dhaka are working in shifts following a duty roster. For this purpose, physicians and nurses working for each hospital have been divided into several groups. Usually, one group is working continuously for a pre-fixed period and then going into quarantine as another group replaces them. Considering this context, randomly selected physicians and nurses serving at the selected hospitals or departments of hospitals during the pre-fixed data collection period will be approached.\n\nThe following selection criteria will be applied for this study.\n\nInclusion criteria\n\nPhysicians and nurses with valid registration numbers\n\nPhysicians and nurses directly serving patients at any selected hospital within the study period\n\nExclusion criteria\n\nPhysicians and nurses who are not in physical contact with patients during the study period\n\nA list of physicians and nurses will be prepared from the selected hospitals, applying the selection criteria for collecting quantitative data, and a self-administered questionnaire will be distributed among them. A group of data collectors will be trained on the questionnaire beforehand. Data collectors will be made available at the hospitals throughout the data collection period for any clarification regarding the questionnaire.\n\nSecond phase: Qualitative data collection. Qualitative data will be collected through in-depth interviews (IDIs) and document review. A strategic sampling strategy with gender balance will be followed for qualitative data collection. Primarily, ten physicians and ten nurses working at the sampled hospitals will be selected through purposive and snowball sampling for interview. Qualitative data will be collected until data saturation.\n\nAt first, the selected potential participants will be sent informed consent forms and a permission letter from the corresponding hospital administration asking for their participation in this study. After obtaining their written approval on consent forms, interviews will officially proceed. Secluded places within hospital premises or adjacent to hospitals as per the convenience of the participant will be the preferred interview locations. Maintaining proper physical distancing and other personal protective measures, IDIs will be conducted and digitally recorded. In addition, verbal and non-verbal expressions of the participants will be recorded by note taking. All audio-taped interviews will be transcribed verbatim immediately after each interview.\n\nDocuments mentioned by the participants during the interview that need further exploration to accomplish research objectives will also be reviewed.\n\nThe data collection plan for collecting qualitative data is shown in Table 1.\n\nFirst phase: Quantitative data collection tool. For quantitative data, a structured questionnaire will be constructed encompassing three aspects of risk perception - cognitive, affective, and psychometric. Cognitive risk perception will be assessed by asking the participants to rate their perceived susceptibility to and perceived severity of COVID-19 using a Likert scale. “Standard questionnaire on risk perception of an infectious disease outbreak” developed by the Municipal Public Health Service Rotterdam-Rijnmond11 and constructs of the health belief model (HBM)12 will be followed to set up the questionnaire on cognitive risk perception. The affective dimension of risk perception will be evaluated through fear, anxiety, trust, and general concerns about COVID-19. To evaluate fear, the Fear of COVID-19 Scale13, a well-validated tool will be used. A validated Bengali version of this tool is also available14. Permission has already been obtained for using this tool for this study. For psychometric risk perception, the psychometric paradigm suggested by Slovic et al. will be used, which focuses on the qualitative dimensions of the perception on COVID-19 such as perceived voluntariness, catastrophic ability, controllability, severity, personal impact, and novelty15. A German risk perception survey questionnaire16 will also be followed to construct the questionnaire for evaluating psychometric paradigm. Questions to evaluate risk communication will be developed based on literature review and supported by the mental theory of risk communication1. Infection prevention and control (IPC) practices will be assessed based on the IPC guideline provided by WHO17 for the healthcare providers. The questionnaire will be pre-tested prior to the data collection among healthcare workers at a primary healthcare facility in Dhaka.\n\nSecond phase: Qualitative data collection tool. A semi-structured guide for IDIs will be prepared, focusing on issues mentioned by the participants in the first phase of the study that need additional explanations. Pilot interviews will be conducted to test the questions in the semi-structured guide and necessary modifications will be made before starting the formal interviews, as recommended by Magnusson and Maracek18.\n\nDocuments shared by the respondents during IDIs will be reviewed. Participants will be asked for two types of documents that are relevant to the study objectives and will reflect their experiences on their risk perception, risk communication and preventive practices: public documents such as office notices, training manuals, guidelines, or protocols; and private documents such as personal notes or logs. For example, participants will be asked to share their experiences about the methods of risk communication during IDIs. If they mention any documents while describing their experience, these will be sought and reviewed.\n\nThe methodological matrix for the study is presented in Table 2.\n\nThe outcome variables to be assessed in this study are presented in Table 3.\n\nFirst phase: Quantitative data analysis. Descriptive analysis will be performed for socio-demographic and other professional characteristics. For continuous variables, mean (standard deviation, SD), median, maximum, and minimum will be calculated. Normality assumption will be made by Shapiro-Wilk test and a p-value of less than 5 percent will be considered as an asymmetric distribution. For categorical variables, rate, percentage, and proportion will be calculated. Perceived risk will be assessed using means with SD and comparisons will be made using the student T-test and analysis of variance (ANOVA) test based on different characteristics such as age, sex, profession, living status, type of healthcare facility, etc.\n\nMultiple linear regression analyses will be performed to determine how much variability of risk perception is predicted by mediums, influencers, and content of risk communication, trust, fear, and anxiety. In addition, the association of risk perception and risk prevention practices will be explored through regression analysis. The role of HBM constructs to explain the healthcare providers’ compliance with IPC guidelines will also be analysed through regression analysis. A p < 0.05 will be used as the level of significance. A window-based statistical software package, preferably SPSS-23, will be used for analysis.\n\nSecond phase: Qualitative data analysis. Qualitative interviews will be transcribed verbatim immediately after interview and will be checked by two researchers via thorough listening of the interview recordings. Data analysis will start immediately after completion of the first transcript while interviews will still be ongoing. A strategic plan will be developed for analysing interviews and documents, based on the generic coding method proposed by Alase19 and suggestions given by Creswell20. Firstly, a qualitative codebook will be developed based on literature review on the research topics. This codebook will contain a list of potential codes with definitions, examples, and instructions on usage. These codes will provide preliminary guidance on coding process and will be changed based on the information learned in the process of data analysis. Secondly, researchers will read interview transcripts and documents several times, organise responses into block of sentences or statements, condense them into meaningful chunky statements, and list repeatedly expressed words or phrases by the participants. Thus, the codebook will be furnished and applied to all interviews and documents. Thirdly, re-reading of and listening to all the documents and interviews will be done and chunky statements will be condensed into fewer non-repetitive non-overlapping statements and encapsulated to produce the central meaning or meaning units of the interviews and documents. Meaning units will then be grouped into sub-categories and then categories. Consequently, themes will emerge that can answer research questions.\n\nAfter analysing and evaluating quantitative and qualitative data separately, triangulation or combination of both data types will be done. Data will be compared and converged following Creswell’s guidance20 to increase data validity, reduce potential bias, minimize limitation, and thus, generate in-depth knowledge on research topics.\n\nCreswell20 put emphasis on establishing validity of the scores and findings from both quantitative and qualitative measures in any mixed method study. With a view to ensuring the accuracy of the overall study findings, some measures are planned to be executed. A well-calculated and adequate sample size will be deployed in both phases of the study. Findings of the quantitative phase will be carefully analysed to find out potential areas that will need further in-depth explanation and will be included in the qualitative data collection tool. Samples will be drawn from the same population for each phase of the study to validate the outcomes. Two different survey interviewer manuals will be prepared in the local language of Bangladesh for the two phases of data collection. A training session will be organized where an adequate number of data collectors will be trained to introduce themselves, explain the purpose of the study, obtain informed consent, administer the data collection tool, preserve confidentiality, and recognize possible negative reactions and respond properly. Fieldwork activities of data collectors will be monitored and supervised regularly to ensure the validity of data. Every transcript and document will be revised thoroughly by two separate researchers to ensure authenticity and credibility. Codes will be cross-checked by different researchers. Consensus on each meaning unit and study finding will be made by all researchers.\n\nEthical approval for this protocol has been obtained from the Institutional Review Board of Bangabandhu Sheikh Mujib Medical University at its 199th meeting (Memo number- BSMMU/2020/6040). All physical data, transcripts and documents will be coded and stored in locked cabinets to secure participants’ information. Only research personnel will be allowed to access the data. The collected information will be used for research purpose only. Several techniques have been adopted to minimize social, physical, and legal risk during the data collection process. Participants will have the right to withdraw from the research at any time. Each of the participants will be given a special identification number for safeguarding confidentiality and protecting anonymity. An informed consent form will be developed containing detailed information about the aim and objectives of the study, the procedure of the study, benefits and risks of participation and the identity of the principal investigator. Informed written consent to participate in the study will be sought from every respondent in both phases of the study.\n\nStudy findings will be disseminated through an online dissemination seminar. In addition, articles will be written and published in international peer reviewed journals and the data set will be shared in the Mendeley Data repository.\n\nData collection in the first phase of this study has been conducted from 17 to 30 May 2020. The second phase of data collection was completed in August. Now, we are undertaking data analysis and report writing.\n\n\nDiscussion\n\nAmidst the COVID-19 pandemic, professional requirements have put healthcare professionals into a pressured situation worldwide. Adams & Walls21 describe this situation in two ways- a stressed health system capacity from overwhelming disease burden and vulnerable healthcare providers. In this context, the sequential explanatory design of this mixed-method study will allow assessment of different dimensions of risk perception among healthcare providers in two phases. At first, the distribution and determinants of risk perception will be evaluated in quantifiable measures among study participants. Then, qualitative dimensions of risk perception will be evaluated in-depth through interviews and document reviews.\n\nIn any situation, analysis of the problem and decision making depends on how an individual perceives the risk. People are often found to use heuristic approaches or mental shortcuts for judging and making decisions without much cognitive effort. Slovic & Peters22 showed that in judgement of risk, perception of risk is negatively correlated to the perceived benefit where effects of or feelings for the activity plays a major role. Favourable effects increase the tolerance for that particular risk, especially under pressured circumstances23. Further, negative emotions such as fear and anger are also related to how a risk is perceived by individuals. This study will evaluate the perception of healthcare providers towards the risk of COVID-19 under two major psychological dimensions suggested by Slovic, Fischhoff, & Lichtenstein24: a) dread risk - the extent to which the risk is perceived to have catastrophic potential, feelings of dread and lack of control; and b) unknown risk - the extent to which a risk is judged to be unobservable, unknown, new, or delayed in producing harmful impact.\n\nIn this study, cognitive risk perception will be evaluated following the theory of HBM. In cognitive behavioural psychology, human behaviour in response to a risk is influenced by several key constructs such as perceived severity of the risk, perceived susceptibility to the risk, perceived benefits of advised action, perceived barriers in performing advised action, cues to action and self-efficacy, as described in HBM12. HBM theorizes that individuals display healthy behaviour if they accurately perceive the associated risk in terms of both severity and susceptibility25.\n\nThis study will use the mental model of risk communication1 to assess how healthcare providers of Bangladesh are being communicated to about the COVID-19 pandemic and how this risk communication affects the perception of risk and resulting preventive behaviors. People, in general, develop a mental model of understanding and interpretation of messages communicated with them based on their cognition1. Furthermore, in any uncertain situation, people generally use heuristics to make decisions, and the utilization of risk information communicated with them greatly depends on the trustworthiness of the information provider5,26. Thus, when the issue at hand is little known, trust plays a major role in shaping perception and deciding engagement in crisis management and control.\n\nThis study will be conducted among physicians and nurses serving at different government hospitals in Dhaka. Thus, the result will not be generalized for healthcare providers working at private hospitals or non-government organizations or hospitals in other parts of the country. A further limitation can be the difference in understanding the questions and Likert scales used in the questionnaire by the participants. To minimise this difference, trained data collectors will be deployed at each study site who can clarify any confusion regarding the questionnaire.\n\n\nConclusion\n\nIn the context of the current COVID-19 pandemic, like the rest of the world, Bangladesh is going through a difficult situation where all sectors of the government, especially the health system, are striving to manage the crisis. Thus, evaluating the methods and elements of risk communication, along with different aspects of perceptions of healthcare providers and their preventive practices regarding COVID-19, will help to understand how risk perception is developed during the time of a pandemic crisis.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Acknowledgements\n\nAuthors acknowledged Professor Golam Hasan Rabbani of Department of Public Health & Informatics, BSMMU for his formative observations and feedbacks that enriched the protocol.\n\n\nReferences\n\nGlik DC: Risk Communication for Public Health Emergencies. Annu Rev Public Health. 2007; 28(1): 33–54. PubMed Abstract | Publisher Full Text\n\nBeck U: Living in the world risk society: A Hobhouse Memorial Public Lecture given on Wednesday 15 February 2006 at the London School of Economics. Economy and Society. 2006; 35(3): 329–45. Publisher Full Text\n\nSlovic P: Perception of risk. Science. 1987; 236(4799): 280–5. Publisher Full Text\n\nJoff H: Risk : From perception to social representation. Br J Soc Psychol. 2003; 42(Pt 1): 55–73. PubMed Abstract | Publisher Full Text\n\nGamhewage G: An Introduction to Risk Communication. Enterprise Risk Management and COSO. 2014. Reference Source\n\nLiu Q, Luo D, Haase JE, et al.: The experiences of health-care providers during the COVID-19 crisis in China: a qualitative study. Lancet Glob Health. 2020; 8(6): e790–e798. PubMed Abstract | Publisher Full Text | Free Full Text\n\nImai T, Takahashi K, Hoshuyama T, et al.: SARS risk perceptions in healthcare workers, Japan. Emerg Infect Dis. 2005; 11(3): 404–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSadati AK, Lankarani MHB, Lankarani KB: Risk Society, Global Vulnerability and Fragile Resilience; Sociological View on the Coronavirus Outbreak. Shiraz E-Medical Journal. 2020; 21(4): e102263. Publisher Full Text\n\nRenn O: Perception of risks. Toxicology Letter. 2004; 149(1-3): 405–13. Publisher Full Text\n\nWHO: WHO Bangladesh COVID-19 Situation Report #12.2020. Accessed on 17 Jun 2020. Reference Source\n\nMunicipal Public Health Service Rotterdam-Rijnmond: Standard questionnaire on risk perception of an infectious disease outbreak. Effective Communication in Outbreak Management for Europe. 2015. Accessed on 17 Jun 2020. Reference Source\n\nGlanz K, Rimer BK, Viswanath K: Health Behavior and Health Education Theory, Research, and Practice. 4th ed. Jossey-Bass: A Wiley Imprint; 2008. Reference Source\n\nAhorsu DK, Lin CY, Imani V, et al.: The Fear of COVID-19 Scale: Development and Initial Validation. Int J Ment Health Addict. 2020; 1–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSakib N, Mamun MA, Bhuiyan AKMI, et al.: Psychometric Validation of the Bangla Fear of COVID-19 Scale : Confirmatory factor analysis and Rasch analysis. Int J Ment Health Addict. 2020; 1–22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSlovic P, Fischhoff B, Lichtenstein S: The Psychometric Study of Risk Perception. Risk Eval Manag. 1986; (2): 3–24. Publisher Full Text\n\nGerhold L: COVID-19 : Risk perception and Coping strategies. Results from a survey in Germany. PsyArXiv. 2020; 1–11. Publisher Full Text\n\nWorld Health Organization: Infection prevention and control during health care when coronavirus disease (COVID-19) is suspected or confirmed.2020. Accessed on 17 Jun 2020.18. Reference Source\n\nMagnusson E, Maracek J: Doing interview-based qualitative research: A learner’s guide. Cambridge University Press; 2015. Reference Source\n\nAlase A: The Interpretative Phenomenological Analysis (IPA): A Guide to a Good Qualitative Research Approach. Int J Educ Lit Stud. 2017; 5(2): 9. Publisher Full Text\n\nCreswell JW: Research design: Qualitative, Quantitative, and Mixed Methods Approaches. 4th ed. Thousand Oaks, CA: Sage; 2014. Publisher Full Text\n\nAdams JG, Walls RM: Supporting the Health Care Workforce during the COVID-19 Global Epidemic. JAMA. 2020; 323(15): 1439–40. PubMed Abstract | Publisher Full Text\n\nSlovic P, Peters E: Risk perception and affect. Current Directions in Psychological Science. 2006; 15(6): 322–5. Publisher Full Text\n\nFinucane ML, Alhakami A, Slovic P, et al.: The affect heuristic in judgments of risks and benefits. J Behav Decis Mak. 2000; 13(1): 1–17. Publisher Full Text\n\nSlovic P, Fischhoff B, Lichtenstein S: The Psychometric Study of Risk Perception. Risk Eval Manag. 1986; (2): 3–24. Publisher Full Text\n\nJanz NK, Becker MH: The Health Belief Model. A decade later. Health Educ Q. 1984; 11(1): 1–47. PubMed Abstract | Publisher Full Text\n\nSlovic P: Perceived Risk, Trust, and Democracy. Risk Analysis. 1993; 13(6): 675–82. Publisher Full Text"
}
|
[
{
"id": "87598",
"date": "07 Jul 2021",
"name": "Salim Mahmud Chowdhury",
"expertise": [
"Reviewer Expertise Public health especially heath system 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 study design is quite appropriate to answer the research questions. Data analysis plan is well described. However, further explanation of the following issues would be helpful for better understanding:\nSix facilities would be selected for the study, but it is not mentioned whether these hospitals would be dedicated facilities for COVID-19 patient management or not. If it is not dedicated facilities, then inclusion and exclusion criteria need to be specified (it would be COVID-19 patients not all patients);\n\nFurther clarification in selecting qualitative interview participants by snowball sampling approach is needed; and\n\nStudy status shows that data collection is completed. However, it is mentioned in other sections that data will be collected which is confusing.\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": "7542",
"date": "06 Jan 2022",
"name": "Marium Salwa",
"role": "Author Response",
"response": "We collected data from both COVID-19 dedicated and non-dedicated hospitals which has been mentioned in the revised manuscript. We initially planned a snowball sampling which was not required later. So, we edited the text accordingly. The entire manuscript has been revised and edited."
}
]
},
{
"id": "82187",
"date": "26 Jul 2021",
"name": "Qaisar Khalid Mahmood",
"expertise": [
"Reviewer Expertise Medical Sociology and Public Health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study protocol is well designed but there are some concerns need to addressed.\n\nHow many healthcare facilities have been dedicated for the treatment of COVID-19 patients.\n\nWhy are you selecting six facilities?\n\nHow the sample will be allocated to the selected facilities.\n\nWill the researchers consider the professional cadres while collecting the data for physicians and nursers.\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? Partly",
"responses": [
{
"c_id": "7543",
"date": "06 Jan 2022",
"name": "Marium Salwa",
"role": "Author Response",
"response": "Acknowledged and incorporated (study settings and study population). The reason for selecting six facilities has been integrated (Participant recruitment and data collection). The sample allocation to the facilities has been described (Participant recruitment and data collection). We did not consider physicians' and nurses' professional cadre."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1335
|
https://f1000research.com/articles/10-337/v1
|
04 May 21
|
{
"type": "Brief Report",
"title": "Male genital injuries attending a tertiary hospital in a western region of Nepal: A two-year snapshot.",
"authors": [
"Alok Atreya",
"Suman Baral",
"Ritesh G Menezes",
"Samata Nepal",
"Alok Atreya",
"Suman Baral",
"Ritesh G Menezes"
],
"abstract": "Background: Male genital injuries are urological emergencies which if not promptly treated with correct therapeutic intervention may lead to chances of loss of fertility due to infections and anatomical disruption of normalcy. This study highlights the clinical scenarios, etiology and outcome of male genital injury cases that were managed at a tertiary care center in Nepal. Such injuries are not frequently encountered as lack of reporting by patients means cases are rare. The present study is the first from Nepal which depicts a comprehensive report on male genital injuries.\n\nMethods: A retrospective analysis of discharge summaries was carried out and the cases of male genital injuries were reviewed during June 2020. All the treated cases during the two-year period from April 2018 to April 2020 at Lumbini Medical College, Nepal were included in the study. Results: There were eight cases of genital trauma admitted and treated during the study period. All the patients were males and age ranged from six to 71 years with a mean age of 33 ± 21.45 years. Fall injury and road traffic accidents (RTA) were observed to be the primary cause in the majority of cases. Conclusion: Superficial injuries to the penis and scrotum do not require surgical exploration and could be managed conservatively. However, deeper and complicated injuries, testicular preservation, the functionality of the part and cosmetic issues are taken into consideration which might require a multi-disciplinary approach. Apart from the medical issues pertaining to genital injuries, there are legal and psychological aspects of such events too which should not be ignored.",
"keywords": [
"genital injuries",
"male",
"Nepal",
"penile fracture",
"scrotal laceration"
],
"content": "Introduction\n\nGenitals play a vital role in providing passage for metabolic waste along with procreation of new life. Protected within the groin they escape trauma; hence injuries are uncommon. However, when injured they are very painful and bleed profusely due to a rich vascular and nerve supply. Genital injuries are seldom life-threatening but may trigger psychological problems1,2.\n\nThere are few case reports from Nepal on male genital injuries, however, detailed studies describing the victim profile, nature and cause of injuries are a rarity. In this regard, the present research is a first from Nepal that attempts to study the cases of male genital trauma in detail to describe the profile of victims, circumstances of injury, modality of treatment and duration of hospital stay.\n\n\nMethods\n\nA retrospective review of discharge summaries from the Department of Surgery of the Lumbini Medical College, Palpa, Nepal over the two-year period from April 2018 to April 2020 was conducted to identify patients treated for perineal injuries. The study included all the cases that had a history of injury to the male genitalia. The cases were identified by manual search based upon the diagnosis and history recorded. Discharge summaries with any of the keywords: penis, penile, scrotum, scrotal, perianal or perineum were selected. The case details were recorded for all the cases included in the study. Specific variables investigated in the study were age and gender of the patient, nature and manner of injury, mechanism of injury, anatomic site, treatment procedure, intra-operative findings and duration of hospital stay. The data thus obtained was then entered into a pre-structured proforma and exported to a Microsoft Excel 2018 spreadsheet and the results were expressed in frequencies, percentages, mean and standard deviation. The research was conducted in the Department of Forensic Medicine during June 2020 at Lumbini Medical College, Palpa, Nepal. The study was approved by the Institutional Review Committee of Lumbini Medical College, letter number IRC-LMC 08-D/020. Furthermore, permission to access and collect departmental data was obtained from the Professor and Head, Department of Surgery.\n\n\nResults\n\nA total of 15,125 cases were admitted during the study period in the Department of General Surgery of whom only eight were cases of genital trauma who were admitted and treated. All the victims were male and age ranged from six to 71 years with a mean age of 33 ± 21.45 years. Fall injury and road traffic accidents (RTA) were observed to be the primary cause for perineal trauma in the majority of cases. Table 1 depicts the characteristics of victims during the study period. Mean duration of hospital stay was 4.37 ± 1.41 days.\n\n\nDiscussion\n\nGenital injuries in women are more common than men and mostly result from childbirth. Perineal tears in women related to childbirth are repaired by obstetricians. Forensic experts too encounter genital injuries in women during medicolegal evaluation of alleged sexual offences. In both circumstances the specific pattern of injury in women can help readily identify the nature of trauma. Genital injuries in women are usually easily repaired. On the other hand, there are diverse circumstances where the projected phallus in males could sustain traumatic injuries. As these traumas are rare, general surgeons may not be familiar with such cases due to a lack of specialist centers and on-site expertise in genito-urethral surgeries3. Management of male genital trauma is always a challenge because of cosmetic and functional requirements.\n\nThe mechanism and severity of injury in male genitalia varies depending upon the location and the state of erectness or flaccidity4. The flaccidity of the pendulous portion of the phallus has a tremendous capacity to resist trauma as it restricts transfer of kinetic energy4. On the other hand, the root which is fixed, is more prone to trauma in straddle injury or pelvic fractures. Due to the increased pressure within, the penis is more vulnerable to injury when erect. The loose and lax genital skin in the males can deform and slide away from the point of contact, however, if injured there is the potential of avulsion stripping entire penile and scrotal skin4.\n\nThe manner of injury in most cases was likely be accidents based upon the cause of injuries. Road traffic injuries and fall from height were the common reasons behind most cases of perineal injuries in the present study. Due to difficult geographical terrain in mountainous Nepal, most earthen and gravel roads are bumpy. Lack of maintenance and repair on the asphalt paved roads means they are also not free of potholes. Sudden jerk of the two wheelers (motorbikes and bicycles) in such potholes was the reason behind blunt scrotal trauma in one of the three victims of road traffic accidents in the present study. The discharge summary of the other victim revealed blunt scrotal trauma leading to hematoma formation due to a sudden jerk while driving a farm tractor. One patient was hit by a motorbike and sustained injuries to the scrotum.\n\nIn rural Nepal, the majority of people are engaged in agricultural activities. Degloving injury of the phallus with fracture was observed in one case, who had given a history of falling from a tree while collecting cattle fodder. Literature reveals grinding and crushing injuries to the scrotum while operating machinery, laceration following animal attack with or without complete amputation, burns, gunshot injuries to mention a few which were not reported in the present study1,4–6.\n\nLiterature reveals that cultural politics from the mid-nineteenth century onwards considered sexuality a distinct entity separated from reproduction7. This became apparent with a concern for the pleasure for women, sexual orientation, sexual rights and norms7. It is argued that to become sexually aroused and experience orgasm is a normal physiological urge similar to eating, breathing or sleeping8. Furthermore, human sexual response is believed to trigger reward centers associated with sex, both sexual or non-sexual in nature8. Sex is not only a coitus for reproduction but it is a sensual pleasure too9,10. As an active agent in a sexual act, males consider the length of the penis to be associated with being macho and vigor. However, studies depict sexual pleasure as more associated with psychological and psychosocial factors rather than physical factors11. Masturbation in men is considered a compensation for unavailable sex12. Aggressive sexual acts were the reason behind penile fracture in two cases in the present study.\n\nAlthough not life threatening, genital injuries in males result in excruciating pain. Furthermore, the location of the injury in the genital area makes the person feel embarrassed and, in the meantime, reluctant to seek medical help. This might be one of the reasons for the under reporting of genital injuries.\n\nMale genital injuries range from simple swelling as a result of blunt trauma to more complicated injuries like avulsion and amputation. A multidisciplinary approach is required to manage a complicated male genital injury which involves a urosurgeon and a plastic surgeon. Psychological counselling is also an integral element in the treatment of such injuries. In cases where the restoration of the anatomical part is not possible in an amputated or a crushed phallus, the psychological trauma the victim will undergo would be more severe as he might not only feel embarrassment but also feel low about losing his masculinity.\n\nThe head and neck of victims are the prime target for perpetrators in cases of violence and homicide. However, genitals are commonly involved in order to intimidate someone13,14. Sexual abuse is rarely reported as the victim is ashamed and embarrassed14. This provides the perpetrator the courage and impunity for further heinous crimes14. Although the intense pain in the genitalia might not last long the psychological trauma is grave which the victim has to bear throughout the rest of his life15,16. The dignity, self-respect and confidence of the person is shattered17. The present study reported a case where a 71-year-old presented with scrotal laceration. The history was suggestive of domestic violence. In another case a 17-year-old sought medical attention after sustaining a penetrating injury of the scrotum with a snooker cue stick. Although the manner of injury sustained in this case is not mentioned, a possibility of sexual violence cannot be ignored. Patriarchal Nepalese society considers homosexual activity as a taboo; shame, guilt and fear of isolation constitute important reasons for not reporting such cases14.\n\nIn accordance with Article 192, Section 2, Subsection ‘F’ of the criminal code of Nepal18, loss of masculinity as a consequence of physical assault is prosecuted under grievous injury and the perpetrator can be given a custodial sentence with 10 years of imprisonment and a fine of one lakh rupees.\n\nProper functioning of sexual organs is important not only for reproduction but for married life too. Male impotency is a ground for divorce in Nepal19. Loss of sexual function due to traumatic injury to the spinal cord or associated nerves as a consequence of accident or intentional trauma is liable for compensation or a fine.\n\nThe retrospective nature of this study has its own inherent limitations. We could not find any previous studies from Nepal to compare the findings of the present study. Long term follow-up of the patients to study late complications in the form of urethral stricture, penile curvature, fertility and sexual functions could not be examined.\n\n\nConclusion\n\nGenital injuries, although a rarity in south east Asian medical literature, are commonly encountered in south east Asian countries including Nepal. Although most of the injuries sustained are accidental in nature, there are instances where the nature of injuries is intentional which could be elucidated by a detailed history. Anatomical repair of the trauma along with psychosocial and legal aspects of the event are not to be ignored. A multidisciplinary team approach is often required in the management of a case of male genital injury which should consist of a general surgeon, urosurgeon, plastic surgeon, psychiatrist and a medicolegal expert.\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\nConsent for publication from patients or their families is not applicable to the present study because the present study is record-based where retrospective review of discharge summaries was done. The Institutional Review Committee of Lumbini Medical College, letter number IRC-LMC 08-D/020 which approved the present study agreed to waive the patient consent in this instance. The anonymity of the patient was maintained and the data were anonymized, however, these alterations did not distort the scientific data.",
"appendix": "References\n\nAhmed A, Mbibu NH: Aetiology and management of injuries to male external genitalia in Nigeria. Injury. 2008; 39(1): 128–133. PubMed Abstract | Publisher Full Text\n\nWille AH, Loening SA: [Management of trauma to the male external genitalia]. Chirurg. 2006; 77(9): 790–9. PubMed Abstract | Publisher Full Text\n\nRees RW, Brown G, Dorkin T, et al.: British Association of Urological Surgeons (BAUS) Consensus Document for the Management of Male Genital Emergencies - Penile Fracture. BJU Int. 2018; 122(1): 26–28. PubMed Abstract | Publisher Full Text\n\nWessells H, Long L: Penile and Genital Injuries. Urol Clin North Am. 2006; 33(1): 117–26, vii. PubMed Abstract | Publisher Full Text\n\nKosutic D, Kisner K: Second-degree chemical burns of the scrotum caused by application of home-made ointment for relief of epididymal pain. Burns. 2008; 34(1): 150. PubMed Abstract | Publisher Full Text\n\nMenezes RG, Kanchan T, Lobo SW, et al.: Male external genitalia injury caused by 'elephant stampede'. Injury. 2008; 39(1): 136. PubMed Abstract | Publisher Full Text\n\nNg D, Chan T, Pothiawala S: A Human Bite on the Scrotum: Case Report and Review of Management in the Emergency Department. J Emerg Med. 2018; 54(4): 537–539. PubMed Abstract | Publisher Full Text\n\nSpurlin WJ: Queer Theory and Biomedical Practice: The Biomedicalization of Sexuality/The Cultural Politics of Biomedicine. J Med Humanit. 2019; 40(1): 7–20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBasson R: Human sexual response. Handb Clin Neurol. 2015; 130: 11–18. PubMed Abstract | Publisher Full Text\n\nEsch T, Stefano GB: The Neurobiology of Love. Neuro Endocrinol Lett. 2005; 26(3): 175–92. PubMed Abstract\n\nRichters J: Bodies, pleasure and displeasure. Cult Health Sex. 2009; 11(3): 225–36. PubMed Abstract | Publisher Full Text\n\nMah K, Binik YM: Are orgasms in the mind or the body? Psychosocial versus physiological correlates of orgasmic pleasure and satisfaction. J Sex Marital Ther. 2005; 31(3): 187–200. PubMed Abstract | Publisher Full Text\n\nRegnerus M, Price J, Gordon D: Masturbation and Partnered Sex: Substitutes or Complements? Arch Sex Behav. 2017; 46(7): 2111–2121. PubMed Abstract | Publisher Full Text\n\nZilkens RR, Smith DA, Mukhtar SA, et al.: Male sexual assault: Physical injury and vulnerability in 103 presentations. J Forensic Leg Med. 2018; 58: 145–151. PubMed Abstract | Publisher Full Text\n\nOosterhoff P, Zwanikken P, Ketting E: Sexual torture of men in Croatia and other conflict situations: an open secret. Reprod Health Matters. 2004; 12(23): 68–77. PubMed Abstract | Publisher Full Text\n\nNorredam M, Crosby S, Munarriz R, et al.: Urologic complications of sexual trauma among male survivors of torture. Urology. 2005; 65(1): 28–32. PubMed Abstract | Publisher Full Text\n\nDaugaard G, Petersen HD, Abildgaard U, et al.: Sequelae to genital trauma in torture victims. Arch Androl. 1983; 10(3): 245–8. PubMed Abstract | Publisher Full Text\n\nThe National Criminal Procedure (Code) Act, 2017. Ministry of Law, Justice and Parliamentary Affairs. Reference Source\n\nThe National Civil (Code) Act, 2017. Ministry of Law, Justice and Parliamentary Affairs. Reference Source"
}
|
[
{
"id": "84442",
"date": "10 Jun 2021",
"name": "Ramkaji Baniya",
"expertise": [
"Reviewer Expertise Meta-analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMinor changes:\n\nAbstract:\n\nFirst paragraph second line: Delete \"chances of\".\n\nFourth paragraph. Please rephrase the sentence as \"Such injuries are not frequently encountered as patient are hesitant to report such injuries.\"\n\nSecond paragraph first line: Delete \"was carried out and \" and replace with \"of\".\n\nMention how the cases were managed briefly in the result section on the abstract and the manuscript.\n\nIntroduction:\n\nFirst paragraph: replace \"genitals play\" with \"Human genitalia plays\".\n\nSecond paragraph: replace \"victim\" with \"patient\".\n\nSecond paragraph: replace \"are a rarity\" with \"have not been done\".\n\nDiscussion:\n\nFirst paragraph, sixth sentence rephrase as \"As these traumas are rare, general surgeons may not be familiar with these urosurgical repair.\"\n\nThird paragraph first sentence. Rephrase a \"the manner of injury in most cares were accidents.\"\n\nThird paragraph. Please rephrase the third, fourth and fifth sentences as \" Due to difficult geographical landscape and poorly maintained roads, road traffic accidents are common in Nepal. Sudden deceleration of a two wheeler on a pothole was the cause of blunt scrotal trauma in one of the three victims of road traffic accidents in the present study.\"\n\nFourth paragraph, second sentence. Change \"falling\" to \"fall\". Delete \"while collecting cattle fodder.\"\n\nI would recommend deleting the fifth paragraph. The last sentence of the paragraph can be added to the fourth paragraph.\n\nSeventh paragraph, last sentence rephrase as \"In cases where the restoration of the anatomical part is not possible in an amputated or a crushed phallus, the psychological trauma to the patient is enormous. Patients are likely to feel embarrassed and sexually incompetent.\" Cite PMID 245608731\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? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7487",
"date": "06 Jan 2022",
"name": "Samata Nepal",
"role": "Author Response",
"response": "Thank you for your time reviewing our manuscript and for your positive feedback. All the changes and edits that you have suggested are incorporated in the revised version."
}
]
},
{
"id": "100604",
"date": "22 Nov 2021",
"name": "Raghvendra Singh Shekhawat",
"expertise": [
"Reviewer Expertise Forensic Pathology"
],
"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\nThese findings have promise for urology emergency clinical care. There should be more information on female genital damage, especially in relation to sexual abuse. The socio-cultural context of genital injuries is well-described by the authors. The authors have also managed to touch on the forensic aspects of the matter by mentioning the appropriate sections of the Nepalese penal code. Longer-term repercussions of such injuries in terms of physical and psychological well-being may be included in the discussion section. While the authors' efforts are praiseworthy, additional research with a larger sample size is suggested.\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? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7486",
"date": "06 Jan 2022",
"name": "Samata Nepal",
"role": "Author Response",
"response": "Thank you for your time reviewing our manuscript and for your positive feedback. As the manuscript focused upon all the cases of male genital injuries treated at Lumbini Medical College, the study did not include genital injuries in females. As this was a prevalence study we did include all the cases during the two-year period (2018- 2020). Although genital injuries are not uncommon, most of the cases go to the specialty hospital with an uro-surgery facility, which is one of the reasons for the small sample size in the present study. We value your suggestion and would conduct future studies with a larger time frame and large sample."
}
]
}
] | 1
|
https://f1000research.com/articles/10-337
|
https://f1000research.com/articles/10-165/v1
|
01 Mar 21
|
{
"type": "Research Article",
"title": "Characteristics and long-term outcomes of childhood glaucoma: a retrospective-cohort study",
"authors": [
"Supawan Surukrattanaskul",
"Pukkapol Suvannachart",
"Sunee Chansangpetch",
"Anita Manassakorn",
"Visanee Tantisevi",
"Prin Rojanapongpun",
"Supawan Surukrattanaskul",
"Pukkapol Suvannachart",
"Anita Manassakorn",
"Visanee Tantisevi",
"Prin Rojanapongpun"
],
"abstract": "Purpose: To evaluate the clinical characteristics and treatment outcomes of patients with childhood glaucoma. Methods: We retrospectively reviewed the data of patients with childhood glaucoma who visited the glaucoma clinics at the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital between January 2008 and January 2018. The diagnosis was based on the Childhood Glaucoma Research Network classification. We recorded their clinical characteristics and requirement of any glaucoma interventions. Results: A total of 691 eyes from 423 patients were included in this study. The patients predominantly comprised boys. The average follow-up duration was 71.3±63.8 months. The mean age at presentation was 3.9±4.4 years. Most patients presented with a high initial intraocular pressure (IOP) of 28.5±11.2 mmHg. Glaucoma associated with non-acquired ocular anomalies (22.9%) was the most common subtype, followed by primary congenital glaucoma (20.8%). We recorded a family history of glaucoma in 6.4% of patients. Most patients had bilateral glaucoma (63.4%) and required at least one intervention (51.5%). The average IOP at the latest follow-up visit was 19.1±10.8 mmHg. All glaucoma types had significantly lower IOP, compared to that at their baselines (all p<0.001). Moreover, most patients had an unfavourable visual acuity (49.5%) at their latest visit. Conclusions: Secondary glaucoma associated with non-acquired ocular anomalies is the most common subtype of glaucoma. All subtypes, including primary glaucoma, were sporadic. The majority of patients had unfavourable visual outcomes. These real-world findings are fundamental to acquire a better understanding of childhood glaucoma.",
"keywords": [
"childhood glaucoma",
"congenital glaucoma",
"paediatric glaucoma",
"Childhood Glaucoma Research Network classification",
"retrospective cohort",
"paediatric eye disease"
],
"content": "Introduction\n\nChildhood glaucoma is a vision-threatening disorder with an incidence of 2.29 to 5.41 per 100,000 individuals1,2. The diagnosis of childhood glaucoma poses some challenges. This can be attributed to the variation in clinical presentations among different age groups. Despite high intraocular pressure (IOP) being the primary cause of glaucomatous damage, an accurate IOP measurement is not always obtained in children. Angle surgery is a common therapy but it is mostly associated with unfavourable outcomes in children, compared to that in adults3.\n\nChildhood glaucoma encompasses several categories of glaucoma. The Childhood Glaucoma Research Network (CGRN) classification was proposed by an international consortium of glaucoma specialists in 2013 to standardise the definition of childhood glaucoma subtypes4. The prevalence of childhood glaucoma differs among ethnicities, ranging from 1:1,250 to 1:68,254 live births5–12. The incidence and clinical characteristics of childhood glaucoma in Thailand have not yet been reported. The Queen Sirikit National Institute of Child Health is one of the largest tertiary centres in Thailand. It is responsible for the treatment of a majority of the complex paediatric cases from all over the country. Paediatric glaucoma clinics have been established by the joint collaboration between the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital, a university-based hospital. These clinics aimed to treat all paediatric glaucoma cases that were referred to the aforementioned hospitals and have been operated by the same group of glaucoma specialists for more than 10 years. We aimed to describe the clinical characteristics and brief long-term treatment outcomes of the large paediatric glaucoma cohorts of the two major referral centres in Thailand.\n\n\nMethods\n\nWe retrospectively reviewed the medical records of all patients who had been examined at the paediatric glaucoma clinics of the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital between January 2008 and January 2018. The patient list was extracted from the hospital database to include all individuals that had at least one visit to the paediatric glaucoma clinic during the above period and/or subjects that had the ICD-10-CM diagnostic codes of Q15.0 and all H40 and H42 categories. The inclusion criteria were patients who aged <16 years at the time of the first clinic visit and met the CGRN glaucoma or glaucoma suspect definition4. Cases with incomplete medical record precluding the diagnosis were excluded. The CGRN definition of glaucoma and suspected glaucoma has been previously described4.\n\nEthical approval was obtained from the Research Ethic Committee of the Queen Sirikit National Institute of Child Health and Faculty of Medicine, Chulalongkorn University (REC.041/2562 and IRB.807/61). The requirement for written informed consent was waived due to the retrospective nature of the study.\n\nWe collected data for the demographic characteristics, initial clinical presentations, and diagnoses. All available clinical information was evaluated and classified according to the Childhood Glaucoma Research Network (CGRN) classification into the following seven groups: (1) primary congenital glaucoma (PCG), (2) juvenile open-angle glaucoma (JOAG), (3) secondary glaucoma following cataract surgery (SCG-C), (4) secondary glaucoma associated with non-acquired systemic disease or syndrome (SCG-S), (5) secondary glaucoma associated with non-acquired ocular anomalies (SCG-O); (6) secondary glaucoma associated with acquired conditions (SCG-A); and (7) glaucoma suspect (GS). The CGRN classification diagram has been illustrated elsewhere4,13.\n\nWe recorded the interventions during the follow-up course and final outcomes, including visual acuity (VA) and IOP at the latest available visit in eyes with a confirmed glaucoma diagnosis (diagnosis group 1 to 6). For glaucoma interventions, we reviewed the data to determine if the subjects had received any incisional surgeries (i.e. trabeculectomy, trabeculotomy, and glaucoma drainage device implantation), cyclodestructive laser procedures (i.e. diode transscleral cyclophotocoagulation, diode laser endoscopic cyclophotocoagulation), or a combination of both at any time point of the follow-up period.\n\nThe best-corrected VAs were determined using the LEA or Snellen chart at 10 feet or 20 feet, respectively. In contrast, VA was graded by the fixation patterns using a central, steady, and maintained (CSM) technique for patients who were too young to determine the pictures or numbers14. The LEA chart symbols were reproduced with permission from Good-Lite Co., Elgin, IL. According to Karr et al.15, the fixation pattern of CSM, CSUM, CUSUM and UCUSUM was estimated as the VA of ≥ 20/30, 20/30–20/100, ≤20/300, and ≤5/200, respectively. We extrapolated the Snellen acuity from the fixation grade with a modification from Karr et al.’s method and classified the VA into the following three groups: (1) favourable: best-corrected VA (BCVA) ≥20/70 or fixation grade of CSM, (2) moderately favourable: BCVA=20/70 to <20/400 or fixation grade of CSUM; and (3) unfavourable: BCVA≤20/400 or fixation grade of CUSUM or UCUSUM.\n\nThe categorical data were presented as counts and percentages. We conducted the Shapiro-Wilk test for the normality of continuous data distribution. The data were reported as means and standard deviations or medians and interquartile ranges, depending on the distribution. We used the analysis of variance to compare the initial IOP among the glaucoma subtypes and the paired t-test to compare the IOP during the initial and latest visit. Furthermore, the Stuart-Maxwell test for marginal homogeneity was used to compare the proportion of matched pairs of the VA during the initial and latest visit. Statistical analyses were performed using Stata 13.0 (Stata Corp, College Station, TX, USA). A P-value <0.05 was deemed statistically significant.\n\n\nResults\n\nThe cohort comprised 423 patients (691 eyes). While 338 patients (532 eyes) were diagnosed with glaucoma, 85 patients (159 eyes) had GS. The average follow-up duration was 71.3±63.8 months (median 50; interquartile range, 22–112 months). Table 1 summarises the baseline characteristics. The average age at presentation was 3.91±4.40 years (median 1.75: interquartile range, 0.25–6.75 years). We recorded a family history of glaucoma in 15 (6.4%) patients. Furthermore, we found a statistically significant predominance of boys in all subjects (P=0.002), PCG (P=0.01), SCG-C (P=0.01), and GS (P=0.04). The mean of initial IOP was 28.5±11.2 mmHg. There was no difference in the initial IOP among the glaucoma subtypes (p=0.52). The most common presentation was cloudy eye (68.2%), which represented leukocoria or corneal haze, and megalocornea (14.5%). Table 2 demonstrates the mode of detection patterns and clinical presentations.\n\nData shown in median (interquartile range).\n\n* Data available in 234, 35, 5, 13, 15, 56, 50, and 60 patients for total, PCG, JOAG, SCG-C, SCG-S, SCG-O, SCG-A, and GS, respectively.\n\n† Data available in 93, 1, 2, 16, 5, 5, 19, and 45 eyes for total, PCG, JOAG, SCG-C, SCG-S, SCG-O, SCG-A, and GS, respectively.\n\n‡ Data available in 426, 71, 14, 39, 34, 41, 71, and 156 eyes for total, PCG, JOAG, SCG-C, SCG-S, SCG-O, SCG-A, and GS, respectively.\n\nIOP, intraocular pressure; SE, spherical equivalence; PCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions; GS, glaucoma suspect.\n\nData shown in number of eyes (%).\n\n* Including eyes from clinical surveillance in known systemic or ocular diseases, clinical surveillance due to family history of glaucoma and other forms of child health screening.\n\nPCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions.\n\nMost patients had bilateral glaucoma (63.4%). Among the 155 eyes of the unilateral cases, there were 72 (46.5%) and 83 (53.6%) right and left eyes, respectively. The diagnosis with significantly higher bilateral presentation included PCG (P=0.01), JOAG (P=0.03), SCG-O (P=0.03), and GS (P<0.001). SCG-S (unilateral 59.4%) and SCG-A (unilateral 53.6%) comprised a higher proportion of unilateral cases. However, the difference was statistically insignificant.\n\nSCG-O was the most common subtype, accounting for 23% of the cohort or 29% of the glaucoma cases. In contrast, JOAG was the least common subtype. Figure 1 depicts the frequency of each glaucoma diagnosis.\n\nPCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions; GS, glaucoma suspect.\n\nThe onset of PCG was neonatal (≤1 month), infantile (>1 to 24 months), and late (>2 years) in 33 (37.5%), 38 (43.2%), and two (2.3%) patients, respectively. However, the onset was undetermined in 15 (17.1%) patients with PCG. Figure 2 outlines the distribution of the anomalies associated with SCG-O, SCG-S, and SCG-A. We could obtain angle data for 56 eyes with SCG-A, of which 44 (78.6%) and 12 (21.4%) eyes had open and closed angles, respectively.\n\nSCG-C was mostly observed following a surgery for a congenital idiopathic cataract (n=19, 57.6%), followed by congenital cataract associated with ocular anomalies or systemic diseases (n=7, 21.2%), and acquired cataract (n=3, 9.1%). There were four patients (12.1%) that the type of cataract could not be specified.\n\nWhile 157 glaucomatous eyes (29.5%) underwent an incisional surgery, 68 eyes (12.8%) underwent a cyclodestructive laser surgery. In contrast, 49 (9.2%) eyes required both incisional and cyclodestructive procedures at any time point during the follow-up period. Figure 3 presents the frequency of glaucoma intervention in each glaucoma type.\n\nPCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions.\n\nSCG-A had the highest proportion of favourable VA at the initial (57.5%) and latest (53.4%) visits. However, JOAG had the highest proportion of unfavourable VA at the initial (53.9%) and latest (73.3%) visits. We observed a higher proportion of unfavourable VA at the latest visit in the overall glaucoma cases (P=0.03), compared to that at the initial visit. A worsening of the VA was primarily observed in the SCG-O group. Despite an approach in the shift, it failed to attain a statistical significance (P=0.07). Moreover, the average IOP was 19.1±10.8 mmHg at the latest visit. All glaucoma types had significantly lower IOPs, compared to the baseline values (all p<0.001). Table 3 shows a comparison of the VA and IOP between the initial and latest visits for each glaucoma type.\n\n* Calculated from the paired data of eyes with available initial visual acuity and latest visual acuity- all glaucoma 253 pairs, PCG 53 pairs, JOAG 13 pairs, SCG-C 42 pairs, SCG-S 17, SCG-O 41 pairs, and SCG-A 87 pairs.\n\n† Calculated from the paired data of eyes with available initial intraocular pressure and latest intraocular pressure- all glaucoma 634 pairs, PCG 129 pairs, JOAG 14 pairs, SCG-C 53 pairs, SCG-S 41, SCG-O 139 pairs, and SCG-A 110 pairs.\n\nPCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions.\n\n\nConclusions/discussion\n\nChildhood glaucoma comprises a group of eye disorders that affect children from their birth with a juvenile onset. Our study had an average follow-up of 6 years. SCG-O (22.9%) was the most common subtype, followed by PCG (20.8%) and SCG-A (18.9%). The condition mostly affected boys, with the majority being bilateral cases, similar to previously published results. Primary glaucoma, both PCG and JOAG, and SCG-O commonly require at least one type of glaucoma intervention. Following the treatment, we observed significant IOP improvements in all subtypes. Nonetheless, half of the cases demonstrated unfavourable VA at the final visit.\n\nExisting literature has reported on a varied distribution of the subtypes2,8–10,12. Most researchers have found a higher prevalence of secondary glaucoma, compared to primary glaucoma. However, reports from Canada6, Egypt9, Great Britain and the Republic of Ireland2, and China7 have found that the majority of cases comprised PCG. The prevalence of secondary glaucoma depends on the prevalence of its aetiology (e.g. childhood cataract, hereditary systemic disease), which can differ among regions and ethnicities. Furthermore, this variation can be explained by the diagnostic criteria and study design. The diagnostic criteria of the studies conducted before 2013 were not based on the CGRN classification. In addition, hospital-based studies tend to have a higher proportion of complex cases, such as patients with syndromic and systemic involvement than those conducted in population-based settings. Table 4 summarises the distribution of childhood glaucoma according to the CGRN classification1,2,5–7,9–12.\n\n* We excluded patients who were glaucoma suspect or had an unknown diagnosis.\n\n† The diagnosis was reclassified from the original articles to follow the CGRN classification.\n\nPCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions\n\nLeukocoria or corneal haze were the leading presenting symptom in PCG (46.9%) and SCG-O (77%) similar with previous studies16–18. Moreover, most patients with JOAG were diagnosed without any symptoms. This could partially explain the most advanced stage at the time of diagnosis and the highest proportion of unfavourable VA outcomes in the aforementioned subtype. High IOP was the leading clue for glaucoma diagnosis. Furthermore, an enlarged corneal diameter was considered an important sign of PCG16.\n\nWe detected a family history of glaucoma in 6.4% of the 234 patients with an available family history. A study by Fung et al. reported on a family history of glaucoma in 17% patients with paediatric GS5. This high rate could be attributed to the tendency of having the eyes checked because of a family history of glaucoma. In our study, an exclusion of the GS cases would have reduced the rate of positive family history from 6.4% to only 5.7% (10 out of 174 patients). This value was half of that reported by Papadopoulos et al. (11%)2. Despite the association of PCG and JOAG with certain mutations19, our cohort revealed a positive family history in none of the PCG cases and in only one JOAG case. Therefore, the PCG cases in Thailand were sporadic rather than inherited.\n\nIn line with the published literature, we found that surgical interventions were mostly required in the primary type of glaucoma, both PCG and JOAG. Moreover, medication was the mainstay of treatment for most secondary glaucoma cases2. In addition, SCG-O cases reported a high rate of surgical intervention. The pathology of the above-mentioned subtype is related to angle dysgenesis, which usually makes it difficult to control the disease.\n\nRamkrishanan et al. reported a significant improvement of VA, which was sustained for at least four years of follow-up20. This was in contrast to the marginally significant worsening of VA observed in our study. This disparity could be attributed to a greater proportion of PCG cases in the study conducted by Ramkrishanan et al. The improvement of VA in their study was attributed to an improved corneal clarity following surgery.\n\nWe found that the SCG-A cases had the most favourable VA at the latest visit and the best initial VA. The majority of the cases included steroid-induced glaucoma, which might be more controllable than the subtypes related to congenital ocular malformations, such as PCG and SCG-O. However, we found an overall worse VA, compared to that reported in previous publications6,11,20. This discrepancy could be explained by the following aspects. First, we documented a high proportion of unfavourable VA during the initial visits. Khitri et al. reported on an association between poor vision at diagnosis and visual impairment (<20/200)21. Second, our cases were diagnosed at an extremely young age, particularly in the PCG (median age 0.5 years) and SCG-O (median age 0.3 years) groups. Studies on the PCG subtype reported on final VA <20/200 in children diagnosed before the age of three months regardless of their IOP levels22,23. It was hypothesised that the earlier presentation reflected the poorer development of the angle. In other words, the disease was more severe. Nevertheless, the study design and definition of unfavourable VA differed among the studies.\n\nOur study had the strength of being a large cohort study with a long follow-up duration. Our data also represents the majority of childhood glaucoma cases in Thailand. However, it had several limitations. First, there were some incomplete data because of the retrospective design. Moreover, information on some clinical examinations, such as VA and IOP could not always be obtained in children at every clinic visit. Second, the long follow-up period resulted in a shift in the IOP measurement methods from a handheld contact tonometer (Tono-Pen; Reichert, New York, USA) to a rebound tonometer (iCare TAO1i, Tiolat Oy, Helsinki, Finland) in extremely young or non-cooperative children. Third, there was inadequate information to clearly identify the cause of unfavourable VA outcomes. Future research should explore this underlying issue.\n\nIn conclusion, data from the referral centres in Thailand showed a higher prevalence of secondary glaucoma than primary glaucoma. Using the CGRN classification, secondary glaucoma associated with non-acquired ocular anomalies was found to be the most common subtype. All subtypes, including primary glaucoma, were sporadic. A majority of the cases had unfavourable visual outcomes. These real-world findings are fundamental data and provide a better understanding of childhood glaucoma.\n\n\nData availability\n\nHarvard Dataverse: Childhood glaucoma, https://doi.org/10.7910/DVN/V3HFNF24.\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\nAponte EP, Diehl N, Mohney BG: Incidence and clinical characteristics of childhood glaucoma: a population-based study. Arch Ophthalmol. 2010; 128(4): 478–482. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPapadopoulos M, Cable N, Rahi J: The British infantile and childhood glaucoma (BIG) eye study. Invest Ophthalmol Vis Sci. 2007; 48(9): 4100–4106. PubMed Abstract | Publisher Full Text\n\nGiangiacomo A, Beck A: Pediatric glaucoma: review of recent literature. Curr Opin Ophthalmol. 2017; 28(2): 199–203. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBeck A, Chang T, Freedman S: Definition, classification, differential diagnosis. In: Weinreb R, Grajewski A, Papadopoulos M, Grigg J, Freedman S, eds. Childhood Glaucoma. Amsterdam Kugler Publication; 2013: 3–10. Reference Source\n\nFung DS, Roensch MA, Kooner KS, et al.: Epidemiology and characteristics of childhood glaucoma: results from the Dallas Glaucoma Registry. Clin Ophthalmol. 2013; 7: 1739–1746. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarsoum-Homsy M, Chevrette L: Incidence and prognosis of childhood glaucoma. A study of 63 cases. Ophthalmology. 1986; 93(10): 1323–1327. PubMed Abstract | Publisher Full Text\n\nQiao CY, Wang LH, Tang X, et al.: Epidemiology of hospitalized pediatric glaucoma patients in Beijing Tongren Hospital. Chin Med J (Engl). 2009; 122(10): 1162–1166. PubMed Abstract | Publisher Full Text\n\nFang Y, Long Q, Guo W, et al.: Profile of pediatric glaucoma patients in Shanghai Eye, Nose and Throat Hospital. Chin Med J (Engl). 2014; 127(8): 1429–1433. PubMed Abstract\n\nMokbel TH, El Hefney EM, Hagras SM, et al.: Childhood glaucoma profile in Dakahelia, Egypt: a retrospective study. Int J Ophthalmol. 2018; 11(4): 674–680. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSenthil SBS, Ganesh J, Krishnamurthy R, et al.: Profile of childhood glaucoma at a tertiary center in South India. Indian J Ophthalmol. 2019; 67(3): 358–365. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaylor RH, Ainsworth JR, Evans AR, et al.: The epidemiology of pediatric glaucoma: The Toronto experience. J AAPOS. 1999; 3(5): 308–315. PubMed Abstract | Publisher Full Text\n\nHoguet A, Grajewski A, Hodapp E, et al.: A retrospective survey of childhood glaucoma prevalence according to Childhood Glaucoma Research Network classification. Indian J Ophthalmol. 2016; 64(2): 118–123. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrajewski Lyra (GL) Foundation for Children with Glaucoma. 2012; Accessed December 25, 2020. Reference Source\n\nWallace DK, Morse CL, Melia M, et al.: Pediatric Eye Evaluations Preferred Practice Pattern®: I. Vision Screening in the Primary Care and Community Setting; II. Comprehensive Ophthalmic Examination. Ophthalmology. 2018; 125(1): P184–P227. PubMed Abstract | Publisher Full Text\n\nKarr D, Scott W: Visual acuity results following treatment of persistent hyperplastic primary vitreous. Arch Ophthalmol. 1986; 104(5): 662–667. PubMed Abstract | Publisher Full Text\n\nKooner K, Harrison M, Prasla Z, et al.: Pediatric glaucoma suspects. Clin Ophthalmol. 2014; 8: 1139–1145. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTamcelik N, Atalay E, Bolukbasi S, et al.: Demographic features of subjects with congenital glaucoma. Indian J Ophthalmol. 2014; 62(5): 565–569. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlanazi FF, Song JC, Mousa A, et al.: Primary and secondary congenital glaucoma: baseline features from a registry at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. Am J Ophthalmol. 2013; 155(5): 882–889. PubMed Abstract | Publisher Full Text\n\nAbdolrahimzadeh S, Fameli V, Mollo R, et al.: Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management. Biomed Res Int. 2015; 2015: 781294. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRamkrishanan R, Mitra A, Kader MA: Surgical and Visual Outcomes of Childhood Glaucoma at a Tertiary Eye Care Center in South India. Asia Pac J Ophthalmol (Phila). 2015; 4(5): 250–258. PubMed Abstract | Publisher Full Text\n\nKhitri MR, Mills MD, Ying GS, et al.: Visual acuity outcomes in pediatric glaucomas. J AAPOS. 2012; 16(4): 376–381. PubMed Abstract | Publisher Full Text\n\nZagora SL, Funnell CL, Martin FJ, et al.: Primary congenital glaucoma outcomes: lessons from 23 years of follow-up. Am J Ophthalmol. 2015; 159(4): 788–796. PubMed Abstract | Publisher Full Text\n\nMacKinnon JR, Giubilato A, Elder JE, et al.: Primary infantile glaucoma in an Australian population. Clin Exp Ophthalmol. 2004; 32(1): 14–18. PubMed Abstract | Publisher Full Text\n\nChansangpetch S: Childhood glaucoma. Harvard Dataverse, V1. 2021. http://www.doi.org/10.7910/DVN/V3HFNF"
}
|
[
{
"id": "80447",
"date": "15 Mar 2021",
"name": "Chungkwon Yoo",
"expertise": [
"Reviewer Expertise glaucoma surgery"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors evaluated the clinical characteristics and treatment outcomes of patients with childhood glaucoma seen in their glaucoma clinics for 10 years. This is a clinically interesting study. However, there are some issues which need to be addressed.\n\nPlease add the specific information on the surgical interventions used and their proportions in each glaucoma subtype: trabeculectomy, goniotomy, trabeculotomy or tube surgery?\n\nCorneal diameters at initial visit?\n\nPoor VA outcome may have resulted from factors other than glaucoma..e.g. inadequately corrected VA or coexisting eye problems. How many of the study eyes had been seen by pediatric ophthalmologists?\n\nYou may analyze the factors associated with poor visual outcome.\n\nGiven the fact that PCG needs surgical management, the proportion of nonsurgically managed eyes among PCG cases was unexpectedly high. What were the reasons for nonsurgical management in those patients? Please address this issue in the discussion section.\n\nThe authors concluded that all subtypes of glaucoma were sporadic. Although the patient-reported or family-reported 'family history of glaucoma' was uncommon, the actual familial occurrence may be more than can be assessed by history taking. Unless each family member was examined for glaucoma, you may not be certain that all subtypes of childhood glaucoma were sporadic.\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": [
{
"c_id": "7580",
"date": "05 Jan 2022",
"name": "Sunee Chansangpetch",
"role": "Author Response",
"response": "The authors evaluated the clinical characteristics and treatment outcomes of patients with childhood glaucoma seen in their glaucoma clinics for 10 years. This is a clinically interesting study. However, there are some issues which need to be addressed. 1. Please add the specific information on the surgical interventions used and their proportions in each glaucoma subtype: trabeculectomy, goniotomy, trabeculotomy or tube surgery?Thank you very much. The table below summarizes the type of surgical procedures for each glaucoma subtype. Please note that some eyes might require more than 1 surgery, thus the overall frequency in this table may differ from the frequency shown in Figure 3. Response: Thank you very much. We have added a table that summarizes the type of surgical procedures for each glaucoma subtype in the revised version of the manuscript. (new Table 3) Please note that some eyes might require more than 1 surgery, thus the overall frequency in this table may differ from the frequency shown in Figure 3. 2. Corneal diameters at initial visit? Response: We apologize for the unclear description. The Refraction, Corneal diameter, Cup to disc ratio listed in Table 1 were the findings from initial visits. We have now updated the table’s footnote. Table 1 - footnote: “Refraction, corneal diameter, and cup to disc ratio were the measurements taken at first visit.” 3. Poor VA outcome may have resulted from factors other than glaucoma..e.g. inadequately corrected VA or coexisting eye problems. How many of the study eyes had been seen by pediatric ophthalmologists? Response: We absolutely agree that several factors contribute to poor VA outcome. At the Queen Sirikit National Institute of Child Health (QSNICH), all children are primarily seen by QSNICH’s pediatric ophthalmologists. The patients are sent to pediatric glaucoma team for glaucoma consultation. They were still followed by pediatric ophthalmologists for other conditions such as refractive error, cataract and other coexisting eye problems. All surgical interventions except for glaucoma procedures are performed by the QSNICH’s pediatric ophthalmologists. However, due to the limitations of a retrospective study, it would be difficult to clearly delineate the cause of poor visual outcome in each patient. We also acknowledge this issue in our Discussion. Conclusions/Discussion - 10th paragraph: “It should be noted that unfavourable VA could be a result from a combination of factors other than glaucoma such as underlying ocular pathology, uncorrected refractive error or amblyopia. As all patients were concomitantly seen by pediatric ophthalmologists, we believe that inadequate orthoptic exercise and inappropriate refractive correction would be less the case. However, due to the limitations of a retrospective study, it would be difficult to clearly delineate the cause of poor visual outcome in each patient.” 4. You may analyze the factors associated with poor visual outcome. Response: Thank you for the astute comment. As suggested by the reviewer, we performed the analysis with an ordinal logistic regression to explore the factors associated with visual outcome. The complete case analysis of 219 eyes showed that less favorable of initial visual acuity and high last IOP were significantly associated with poor visual outcome. In comparison to SCG-C, PCG, JOAG and SCG-O diagnoses were significantly associated with poor visual outcome. No significant risk of poor visual outcome was identified for the SCG-S and SCG-A groups when compared to the SCG-C group. We have updated the Methods and Results sections to include the description of the statistical analysis and the table in the revised manuscript. (new Table 5). 5. Given the fact that PCG needs surgical management, the proportion of nonsurgically managed eyes among PCG cases was unexpectedly high. What were the reasons for nonsurgical management in those patients? Please address this issue in the discussion section. Response: Thank you for the comment. The primary reason for not receiving surgical intervention was that the IOP could be controlled with medications. All patients with evidence of high IOP were offered surgical intervention (trabeculotomy and goniotomy) for PCG. The option of surgical intervention was discussed with the families of those who had previously been treated with medication. After seeing the well-controlled IOP, some parents preferred to continue with the medication. For additional information of the patients who did not have glaucoma intervention, please refer to the response to reviewer 2’s query No.2. We have now included this explanation in the 6th paragraph of the Discussion. 6. The authors concluded that all subtypes of glaucoma were sporadic. Although the patient-reported or family-reported 'family history of glaucoma' was uncommon, the actual familial occurrence may be more than can be assessed by history taking. Unless each family member was examined for glaucoma, you may not be certain that all subtypes of childhood glaucoma were sporadic. Response: We thank the reviewer for the insightful comment and agree with the suggestion. We have removed the conclusion in the Abstract regarding this issue and have modified the Discussion to avoid misleading. Conclusions/Discussion - 4th paragraph: “The true frequency of familial glaucoma, however, may be higher, as the data were available for only 55% of our patients. In addition, getting a family history without examining each family member tends to underestimate the actual occurrence of glaucoma in the family.”"
}
]
},
{
"id": "80450",
"date": "01 Apr 2021",
"name": "Kazuhiko Mori",
"expertise": [
"Reviewer Expertise glaucoma"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article successfully reports the clinical characteristics and treatment outcomes of patients with childhood glaucoma from the real-world large data of 10 years in Thailand.\nThe statistics used are appropriate and the interpretations are consistent. Overall findings in this study are important to the field. However, there are a few points need to be fixed, and discussion needs more work to improve the interpretation of the results.\nMajor comments:\nThe discussion about the reason of unfavorable visual outcome is insufficient. Authors should dig much deeper into the reason of visual impairment of their patients, whether it was really unavoidable or not. For example, JOAG group mainly seems to have clear cornea where disc is visible (14/15) and good IOP control (25.6 to 15.0 mmHg), however, the unfavorable cases were increasing compared to the initial VA. What caused the unwilling visual outcome? Is it due to the corneal haziness or glaucoma progression? Inadequate orthoptic exercises? Or merely gathering of very severe cases to the tertiary hospitals? If there are any possible clues or suggestions to improve, it might be a good help for the readers who are struggling under the same situation.\n\nAs the authors mentioned, surgical interventions were mostly required in the primary type of glaucoma, both PCG and JOAG, and especially SCG-O. However, from this study, no glaucoma intervention was performed to 46.7, and 42.3% of the patients of JOAG and SCG-O, respectively. Explain the reason why almost a half of the patients did not need the surgical intervention.\nMinor comments:\nNeed the details of surgical procedures.\n\nAre there any relations between the laterality and visual outcome?\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": [
{
"c_id": "7581",
"date": "05 Jan 2022",
"name": "Sunee Chansangpetch",
"role": "Author Response",
"response": "This article successfully reports the clinical characteristics and treatment outcomes of patients with childhood glaucoma from the real-world large data of 10 years in Thailand. The statistics used are appropriate and the interpretations are consistent. Overall findings in this study are important to the field. However, there are a few points need to be fixed, and discussion needs more work to improve the interpretation of the results. Response: We appreciate the reviewer's comment. Major comments: 1. The discussion about the reason of unfavorable visual outcome is insufficient. Authors should dig much deeper into the reason of visual impairment of their patients, whether it was really unavoidable or not. For example, JOAG group mainly seems to have clear cornea where disc is visible (14/15) and good IOP control (25.6 to 15.0 mmHg), however, the unfavorable cases were increasing compared to the initial VA. What caused the unwilling visual outcome? Is it due to the corneal haziness or glaucoma progression? Inadequate orthoptic exercises? Or merely gathering of very severe cases to the tertiary hospitals? If there are any possible clues or suggestions to improve, it might be a good help for the readers who are struggling under the same situation. Response: Thank you for bringing up this important issue. As also mentioned by another reviewer, we agree that the factors associated with visual outcome would be worth exploring. The ordinal regression analysis showed that less favorable of initial visual acuity (VA) and high last IOP were significantly associated with poor visual outcome. In comparison to SCG-C, PCG, JOAG and SCG-O diagnoses were significantly associated with poor visual outcome. No significant risk of poor visual outcome was identified for SCG-S and SCG-A when compared to SCG-C. As all patients were primarily seen by pediatric ophthalmologists (please refer to the response to reviewer 1’s query No.3), we believe that inadequate orthoptic exercise and inappropriate refractive correction would be less the case. However, we could not assess the adherence to the treatment and follow-up with the pediatric ophthalmologists. To elaborate more on the progression to unfavorable visual impairment, we further investigated the change of the VA group. Table 6 in the revised manuscript showed that most patients had no change in the VA group between the initial VA and the last VA. Most eyes with unfavorable last VA had already presented with unfavorable VA. The SCG-C tended to have an improvement of the VA. On the other hand, SCG-O had the highest proportion of worsening VA. There was no improvement in the VA group in any of the JOAG. There were 12 eyes of SCG-O that showed worsening of the VA to the unfavourable VA at the latest visit. Almost all cases had limited visual potential due to cornea and/or anterior segment anomalies (Peters anomaly, microcornea and sclerocornea). These patients had their initial visit at a young age (all < 6 years) and the initial VA was recorded as ‘fix and follow’, which was classified in this study as ‘favourable VA’. However, the final VA ranged from HM to FC 3 ft, which could be explained by their cornea and/or anterior segment conditions. There were 2 cases of congenital ectopia lentis. One of them underwent cataract surgery without IOL implantation. The other developed retinal detachment after trabeculectomy. Both had the final VA of hand motion. Among the 13 JOAG with available initial visual acuity and latest visual acuity, there were 2 eyes that showed worsening of the VA group. The first case presented with a C:D ratio of 0.9 in the right eye. The contralateral eye had no light perception at the presentation. The patient had successful trabeculectomy in the right eye but lost to follow-up afterwards. She came back with the vision of PL and full disc cupping. The second case had an initial C:D ratio of 0.95 and an initial VA of 20/100. Although the patient responded well to the treatment and the IOPs were in the low teens, the VA slowly got worse. After approximately 12 years, the last VA was hand motion. Regarding 7 eyes with unfavourable final VA and unfavourable initial VA, all C:D ratios at presentation were at least 0.9. Our data suggested that the initial VA and glaucoma stage at presentation were the main factors determining the unfavourable VA outcome. The underlying ocular abnormalities tended to limit the visual potential in SCG-O, the anterior segment dysgenesis in particular. We now mentioned this point in the 9th and 10th paragraph of the Discussion. 2. As the authors mentioned, surgical interventions were mostly required in the primary type of glaucoma, both PCG and JOAG, and especially SCG-O. However, from this study, no glaucoma intervention was performed to 46.7, and 42.3% of the patients of JOAG and SCG-O, respectively. Explain the reason why almost a half of the patients did not need the surgical intervention. Response: We thank the reviewer for the comment. Although PCG, JOAG and SCG-O had the high rate of surgical intervention, a high proportion of eyes that had no glaucoma interventions was observed in our study. The primary reason for not receiving surgical intervention was that the IOP could be controlled with medications. All patients with evidence of high IOP were offered surgical intervention (trabeculotomy and goniotomy) for PCG. The option of surgical intervention was discussed with the families of those who had previously been treated with medication. After seeing the well-controlled IOP, some parents preferred to continue with the medication. Unlike PCG, the surgical intervention was not necessarily offered to all SCG-O and JOAG patients. The decision to perform surgery in SCG-O was mainly based on the IOP and visual prognosis. Conservative treatment with medications was preferred If there was very limited vision potential such as nystagmus or visual acuity of light perception. For JOAG, the approach was quite similar to that for adult glaucoma. The majority of cases that did not receive glaucoma intervention underwent selective laser trabeculoplasty and were able to achieve target IOPs, though with medications. We have now explained these reasons in the 6th paragraph Discussion. Additional information of the patients that had no glaucoma intervention was listed below. PCG: 38 eyes from 21 patients 9 eyes (5 patients) were lost to follow-up. 2 eyes (2 patients) underwent evisceration due to severe buphthalmos. (One eye also had the ruptured globe.) 1 eye (1 patient) had severe corneal ulcer and became phthisis. 2 eyes (1 patient) developed late-onset infantile cataract. After lens aspiration the IOP went down to mid teen with single medication. 16 eyes (8 patients) had the presenting IOP of less than 20 mmHg because they were treated with medications before the referral. The parents prefer to continue with the medication. 6 eyes (3 patients) had high presenting IOP and were scheduled for the surgery. After initiating the medication during, the IOP went down to mid teen with 2-3 medications and the parents refused to have the surgery. 2 eyes (1 patients) had no specified reason in the medical record. SCG-O: 66 eyes from 49 patients 4 eyes (4 patients) were lost to follow-up. 1 eye (1 patient) underwent evisceration due to impending ruptured descematocele. 30 eyes (17 patients) had the presenting IOP of less than 20 mmHg because they were treated with medications before the referral. 8 eyes (5 patients) had high presenting IOP. After initiating the med, the IOP went down to mid teen with 2-3 medications. 20 eyes (15 patients) had initial poor visual prognosis, inoperable condition (e.g. marked thin sclera) or contraindication for surgery (e.g. underlying heart disease) 3 eyes (3 patients) had no specified reason in the medical record. JOAG: 7 eyes from 4 patients 2 eyes (1 patient) were lost to follow-up. 3 eyes (2 patients) received selective laser trabeculoplasty. 2 eyes (1 patient) had IOP lowered to teen by medications. Minor comments: 1. Need the details of surgical procedures. Response: Thank you very much. We have now included a table that summarizes the type of surgical procedures for each glaucoma subtype. (new Table 3) Please note that some eyes might require more than 1 surgery, thus the overall frequency in this table may differ from that showed in Figure 3. 2. Are there any relations between the laterality and visual outcome? Response: Thank you for the comment. The statistical analysis with chi-square test showed no association between the laterality and visual outcome (p=0.62)."
}
]
},
{
"id": "80446",
"date": "01 Apr 2021",
"name": "Chengguo Zuo",
"expertise": [
"Reviewer Expertise Glaucoma"
],
"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 interesting study analyzed the clinical characteristics and treatment results of patients with childhood glaucoma who had visited the glaucoma clinics at the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital within 10 years, and provided effective data and analysis for a better understanding of children’s glaucoma in Thailand. There are several questions that need to be answered:\nIn the \"Results\" of the \"Abstract\", “Most patients presented with a high initial intraocular pressure (IOP) of 28.5±11.2 mmHg.” Does the patients here refer to all patients or just for the patients with a high initial IOP?\n\nIn the “Results”, you described that “The average age at presentation was 3.91±4.40 years (median 1.75: interquartile range, 0.25–6.75 years).” But in the “Table 1”, the average age at presentation of the total patients is 1.6(0.3 to 6.8) years. Please give a more detailed explanation here or check data again.\n\nIn this study, the authors only collected the family history of 234 of the 423 patients, as you described that “We detected a family history of glaucoma in 6.4% of the 234 patients with an available family history.” in the “Conclusions/discussion”. We suggest that the description of this in the previous part “Result” that “We recorded a family history of glaucoma in 15 (6.4%) patients” need to be added the information that the data was from 234 patients, so as not to cause misleading or doubt. Besides, when analyzing the family history of patients, the author did not analyze the fact that the family history of not all the patients had been collected. This will inevitably lead to a certain degree of bias. Without analyzing this, the conclusion that” Therefore, the PCG cases in Thailand were sporadic rather than inherited.” could be not that reliable.\n\nThere are several places in the article that need to be supported by the literature: a）：In the “Conclusion” that “The condition mostly affected boys, with the majority being bilateral cases, similar to previously published results.”b）：In the “Conclusion” that “In addition, SCG-O cases reported a high rate of surgical intervention.”\n\nIn the “Conclusion”, you described that “This disparity could be attributed to a greater proportion of PCG cases in the study conducted by Ramkrishanan et al.” Please Please provide the PCG ratio of this research and the comparison with that of your study to compare the difference between the two more intuitively.\n\nIn the description SCG-A had the most favourable VA at the latest visit and the best initial VA, you described that “The majority of the cases included steroid-induced glaucoma, which might be more controllable than the subtypes related to congenital ocular malformations, such as PCG and SCG-O.” But from Figure 2, steroid-induced glaucoma accounts for 29%, which is not so high. Does the authors mean “The majority of the cases such as steroid-induced glaucoma, which might be more controllable than the subtypes related to congenital ocular malformations…”?\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": "7579",
"date": "05 Jan 2022",
"name": "Sunee Chansangpetch",
"role": "Author Response",
"response": "This interesting study analyzed the clinical characteristics and treatment results of patients with childhood glaucoma who had visited the glaucoma clinics at the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital within 10 years, and provided effective data and analysis for a better understanding of children’s glaucoma in Thailand. There are several questions that need to be answered: 1. In the \"Results\" of the \"Abstract\", “Most patients presented with a high initial intraocular pressure (IOP) of 28.5±11.2 mmHg.” Does the patients here refer to all patients or just for the patients with a high initial IOP? Response: We apologize that the sentence was not clear. The IOP of 28.5±11.2 mmHg referred to all patients’ IOP. We have modified the sentence as follows: Abstract: “Most patients presented with a high initial intraocular pressure (IOP). The average initial IOP of all patients was 28.5±11.2 mmHg.” 2. In the “Results”, you described that “The average age at presentation was 3.91±4.40 years (median 1.75: interquartile range, 0.25–6.75 years).” But in the “Table 1”, the average age at presentation of the total patients is 1.6(0.3 to 6.8) years. Please give a more detailed explanation here or check data again. Response: Thank you very much for catching this. The median age at presentation was 1.58. We have corrected the error in the Results: Results: “The average age at presentation was 3.91±4.40 years (median 1.58: interquartile range, 0.25–6.75 years).” 3. In this study, the authors only collected the family history of 234 of the 423 patients, as you described that “We detected a family history of glaucoma in 6.4% of the 234 patients with an available family history.” in the “Conclusions/discussion”. We suggest that the description of this in the previous part “Result” that “We recorded a family history of glaucoma in 15 (6.4%) patients” need to be added the information that the data was from 234 patients, so as not to cause misleading or doubt. Besides, when analyzing the family history of patients, the author did not analyze the fact that the family history of not all the patients had been collected. This will inevitably lead to a certain degree of bias. Without analyzing this, the conclusion that” Therefore, the PCG cases in Thailand were sporadic rather than inherited.” could be not that reliable. Response: We agree with the reviewer’s comment. We have added that the family history data was obtained from 234 patients and removed the conclusion of the sporadic nature in the Abstract to avoid misleading. The Conclusions/Discussion section have also been modified. Abstract - results: We recorded a family history of glaucoma in 6.4% of patients of the 234 patients with an available family history. Conclusions/Discussion - 4th paragraph: “The true frequency of familial glaucoma, however, may be higher, as the data were available for only 55% of our patients. In addition, getting a family history without examining each family member tends to underestimate the actual occurrence of glaucoma in the family.” 4. There are several places in the article that need to be supported by the literature: a）：In the “Conclusion” that “The condition mostly affected boys, with the majority being bilateral cases, similar to previously published results.”b）：In the “Conclusion” that “In addition, SCG-O cases reported a high rate of surgical intervention.” Response: Thank you for the comment. The following references have been added. To (a): 16. American Academy of Ophthalmology. Glaucoma in Children and Adolescents. In: Tanna AP, Lin SC, Boland MV, et al., eds. Basic and Clinical Science Course Section 10 Glaucoma. San Francisco: American Academy of Ophthalmology; 2020. To (b): 5. Fung DS, Roensch MA, Kooner KS, Cavanagh HD, Whitson JT. Epidemiology and characteristics of childhood glaucoma: results from the Dallas Glaucoma Registry. Clinical Ophthalmology. 2013;7:1739-1746. 5. In the “Conclusion”, you described that “This disparity could be attributed to a greater proportion of PCG cases in the study conducted by Ramkrishanan et al.” Please Please provide the PCG ratio of this research and the comparison with that of your study to compare the difference between the two more intuitively. Response: We appreciate the reviewer’s comment. We have included the proportion of Ramkrishanan’s study in comparison with our study. Conclusions/Discussion - 7th paragraph: “This disparity could be attributed to a greater proportion of PCG cases in the study conducted by Ramkrishanan et al. (Ramkrishanan et al. 73.3% vs our study 20.8%).” 6. In the description SCG-A had the most favourable VA at the latest visit and the best initial VA, you described that “The majority of the cases included steroid-induced glaucoma, which might be more controllable than the subtypes related to congenital ocular malformations, such as PCG and SCG-O.” But from Figure 2, steroid-induced glaucoma accounts for 29%, which is not so high. Does the authors mean “The majority of the cases such as steroid-induced glaucoma, which might be more controllable than the subtypes related to congenital ocular malformations…”? Response: Thank you. The sentence has been revised as suggested. Conclusions/Discussion - 8th paragraph: “The majority of the cases included steroid-induced glaucoma, trauma and uveitis. In general, acquired conditions might be more controllable than the subtypes related to congenital ocular malformations, such as PCG and SCG-O.”"
}
]
}
] | 1
|
https://f1000research.com/articles/10-165
|
https://f1000research.com/articles/10-614/v1
|
20 Jul 21
|
{
"type": "Brief Report",
"title": "Cerebrospinal fluid neurofilament light levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment",
"authors": [
"Katharina Iwan",
"Nina Patel",
"Amanda Heslegrave",
"Mina Borisova",
"Laura Lee",
"Rebecca Bower",
"Sara E. Mole",
"Philippa B. Mills",
"Henrik Zetterberg",
"Kevin Mills",
"Paul Gissen",
"Wendy E. Heywood",
"Katharina Iwan",
"Nina Patel",
"Amanda Heslegrave",
"Mina Borisova",
"Laura Lee",
"Rebecca Bower",
"Sara E. Mole",
"Philippa B. Mills",
"Henrik Zetterberg",
"Kevin Mills",
"Paul Gissen"
],
"abstract": "Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.",
"keywords": [
"Neuronal Ceroid lipofuscinosis",
"Enzyme replacment therapy",
"Neurofilament light"
],
"content": "Introduction\n\nClassic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is the second most common type of neuronal ceroid lipofuscinosis (NCL), a group of inherited progressive neurodegenerative diseases in children.1 The classical form of CLN2 disease presents in most patients with early language delay followed by onset of seizures at around three years of age, ataxia, motor and cognitive decline, loss of vision, with death by early adolescence. Atypical forms of CLN2 exist, where patients may present at an older age and with much slower pace of neurodegeneration.2 It is estimated that atypical patients constitute 10-20% of the total CLN2 patient cohort, although this may vary in different populations.\n\nIn the UK, 5-6 children are diagnosed with CLN2 disease each year, and it is estimated that 30-50 children are currently living with the disease.3 CLN2 disease is caused by mutations in the tripeptidyl peptidase 1 (TPP1) gene, which result in either loss or deficiency of the TPP1 lysosomal hydrolase. TPP1 deficiency leads to the characteristic autofluorescent neuronal ceroid lipofuscin accumulation of NCL.4\n\nBrineura (cerliponase alfa) is a human recombinant form of TPP1 enzyme replacement therapy (ERT) that was approved for treatment in the US and EU in 2017. It is administered as an intracerebroventricular infusion every two weeks.5 The effect of ERT on functional decline can be measured using the CLN2 Disease Clinical Rating Scale (CLN2 CRS).6 Patients on ERT are less likely to have an unreversed two-point decline in a combined motor and language function score when compared to untreated patients.5 Currently the only way to monitor treatment is through the CLN2 CRS as there are no biomarkers used to monitor neurodegeneration. In this study, we measured neurofilament light (NfL) a known biomarker of neuroaxonal damage and degeneration7 in patients undergoing ERT either in the initial 18 weeks of treatment or, in another cohort of patients, who were receiving ERT for at least one year, in whom we monitored NfL over the following 12-18 month period. This allowed us to determine the timing of the response of NfL levels in patients on ERT.\n\n\nMethods\n\nThe collection of samples for this study has ethical approval (13/LO/0168; IRAS ID 95005; London-Bloomsbury Research Ethics Committee) and Health Research Authority (HRA) approval and all participants provided informed written consent to participate. The study was conducted between May 2019 to October 2020 at Great Ormond Street hospital, UCL Institute of Child Health and UCL Dementia Research Institute.\n\nAll patients were receiving intraventricular infusion of Brineura (cerliponase alfa) from BioMarin pharmaceutical.8 Samples were collected for two groups of patients. A short-term/acute change (n = 5) group consisted of samples from patients at first dose of ERT and followed from 20-80 days after the start of treatment. A long-term group (n = 6) consisted of samples collected from patients who had been receiving ERT for approximately one year. Samples were collected over an additional 12-18 month period from one year of ERT. CLN2 score was performed as in Schulz et al, 2018.5 The lowest initial combined CLN2 score was 2 in the short-term group and 1 in the long-term group. All patients receiving Brineura infusions at Great Ormond Street Hospital were included into the study provided the families signed an informed consent form.\n\nVentricular CSF samples were acquired from surplus material taken for routine infection monitoring. Collected CSF was frozen at -80°C within 24 hours of collection. CSF NfL protein concentration was measured on a Simoa HD-X analyser using the Simoa NF-light Advantage assay kit (Quanterix, Billerica, MA) after being diluted 100×, as per manufacturer’s instructions. The measurements were performed in one round of experiments using one batch of reagents with the analyst blinded to clinical data. Intra-assay coefficients of variation, monitored using internal quality control samples, were 0.3-8.9%.\n\nResults were exported to Microsoft Excel15 and data analysed using GraphPad Prism v 6 for statistical analysis. Non-parametric paired t-test was applied.\n\n\nResults and discussion\n\nNfL had first been suggested as a biomarker for future treatment-monitoring of CLN3 disease as elevated CSF (2096 ± 1202 pg/ml) has been observed in patients compared to controls (345 ± 610 pg/ml).9 Serum NfL concentration in CLN2 disease has been described to decrease with treatment in canine models and paediatric patients where levels were 48-fold higher than controls pre-treatment but decreased by 50% each year over more than three years of treatment. CSF NfL was monitored for the canine model and observed to correlate with serum NfL; however, the degree of change of NfL with disease progression was observed to be greater in CSF (by 100%) than in serum (56%).10 A healthy paediatric NfL range has so far not been defined. NfL is observed to increase with age with the lowest range observed for 20-25 year olds as <300 pg/ml.11 Therefore, values above 300 pg/ml are likely pathological.\n\nWe describe here the analysis of two separate patient cohorts collected to assess short-term change (n = 5) and long-term change (n = 6) in clinical parameters and CSF NfL over 1-2 years after the first infusion of cerliponase alfa. We observed levels of NfL at the first infusion/baseline over 2000 pg/ml for all patients. Patient information is given in Table 1.\n\nIn the first cohort of “treatment-naïve” patients, the post-treatment samples collected 2-3 weeks after the first cerliponase alfa infusion showed that NfL had decreased in two patients (Figure 1) but these values were still far higher than levels observed for patients on more than two years of ERT (Figure 2A). The other three patients showed either no change or an increase in NfL.\n\n(B) Paired analysis of the median values of NFL at 1-1.15 of treatment vs 2.5-3 yrs treatment. *p < 0.05 Wilcoxon paired t-test.\n\nIn this cohort of six patients, the patient (1488) with the lowest combined language and motor CLN2 score had the highest NfL level. Patient 1498 has an atypical form of the disease with later onset of symptoms and much slower progression and had the lowest initial NfL levels in this cohort, but this increased after start of treatment. This increase is likely due to NfL levels being affected by an intracerebroventricular (ICV) device infection and repeat surgery in this patient, as NfL is a non-specific marker of neuroinflammation.\n\nThe second (long-term ERT) cohort started their treatment prior to approval of Brineura and had been receiving infusions as part of a compassionate use programme for a year before collection of CSF. For this group CSF began to be collected from 299 days (~10 months) to 600 days (~1.64 years) after the start of treatment and then continued to be collected up to 990 days (2.7 years) post treatment. Most patients had lower levels of NfL that were in the normal adult range (<300pg/ml), apart from two patients. These two patients (1305 and 1306) had more severe movement disorders compared with the other patients. Improvement in involuntary movements temporarily correlated with a decrease of NfL over the next 18 months. Patient 1128 has a particularly severe seizure disorder with poor response to pharmacotherapy. Their NfL level after one year of treatment was low suggesting that NfL level is not likely to be a useful biomarker of seizure control. This observation is supported by a previous study which reported that serum NfL was not altered in children with febrile seizures.12 However, it had also previously been reported that NfL may reflect the contribution of seizure status to CLN3 disease severity.13\n\nThe lowest NfL levels in this cohort was in the atypical patient 667. For the long-term ERT cohort, the one-year NfL levels fluctuated moderately before dropping to their lowest levels at two years after start of ERT. When taking the median value of 1-1.5 yrs post-ERT and comparing with levels >2.5 years after ERT there was a significant decrease in NfL levels (p < 0.03 by paired t-test (Figure 2B). This confirms previous observations where serum NfL levels were seen to continually decrease over three years on treatment.10 That study also revealed that some patients’ early serum NfL levels (approximately two months post-ERT) increased and did not begin to decline until nearly one year on treatment. This previous study and our observations here for CSF NfL indicate that in some patients it may take up to a year to start seeing the positive effect of ERT on preventing axonal damage. Moreover, the complete normalisation of NfL levels is likely to take longer. Once the levels normalise, they are likely to stay in the normal range which corresponds to the stabilisation of the patients’ clinical parameters.\n\n\nConclusions\n\nCSF NfL levels are increased in CLN2 disease patients with lower levels observed in patients with an atypical phenotype therefore Nfl levels potentially indicate disease progression and show the effect of treatment with Brineura, correlating with the decline of neuroaxonal damage to very low levels after 2.8 years of ERT. However, in some patients we observed a delayed decline to low levels in Nfl compared to other CLN2 patients. CSF NfL may therefore be a good marker to identify these patients who could then receive an adjusted treatment regimen to achieve a faster improved clinical outcome. The results reported here are also relevant to interpretation of NfL changes with time in a clinical trial of potentially disease-modifying drug candidates in adult neurodegeneration.14\n\n\nData availability\n\nUCL data repository: CSF Nfl results CLN2 disease. https://doi.org/10.5522/04/14822463.v1.15\n\nThe project contains CSF Nfl results for Group 1 and Group 2 (CSF Nfl CLN2 disease Iwan etal.xlsx).\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 authors would like to thank the Batten Disease Support and Research Association (BDSRA), USA, Noah's Hope/Hope for Bridget and Drew's Hope for funding this project. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. UK Dementia Research Institute at UCL and a Wellcome Trust Multi-User Equipment Grant to Henrik Zetterberg and Amanda Heslegrave.\n\n\nReferences\n\nKohlschütter A, Schulz A, Bartsch U, et al.: Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs . 2019; 33: 315–325. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchmidtke C, et al.: Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking. J Biol Chem . 2019; 294: 9592–9604. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBatten Disease Family Association: 2014; Vol. 2021.\n\nSpecchio N, Pietrafusa N, Trivisano M: Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy. Ther Clin Risk Manag . 2020; 16: 213–222. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchulz A, et al.: Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med . 2018; 378: 1898–1907. PubMed Abstract | Publisher Full Text\n\nKathleen W, Wyrwich AS, Miriam N, et al.: Jacoby and Alfried Kohlschütter. An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease. J Inborn Errors Metabolism Screening. 2018; 6, 1–7.\n\nKhalil M, et al.: Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol . 2018; 14: 577–589. PubMed Abstract | Publisher Full Text\n\nMarkham A: Cerliponase Alfa: First Global Approval. Drugs . 2017; 77: 1247–1249. PubMed Abstract | Publisher Full Text\n\nDang Do AN, et al.: Neurofilament light chain levels correlate with clinical measures in CLN3 disease. Genet Med: official journal of the American College of Medical Genetics . 2021; 23: 751–757. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRu Y, et al.: Neurofilament light is a treatment-responsive biomarker in CLN2 disease. Ann Clin Transl Neurol . 2019; 6: 2437–2447. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVagberg M, et al.: Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction. PloS One . 2015; 10: e0135886. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEvers KS, et al.: Serum Neurofilament Levels in Children With Febrile Seizures and in Controls. Front Neurosci . 2020; 14: 579958. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbdennadher M, et al.: Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures. J Inherit Metab Dis. 2021. PubMed Abstract | Publisher Full Text\n\nRaket LL, et al.: Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer's disease. Alzheimers Dement (Amst) . 2020; 12: e12099. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIwan K, et al.: CSF Nfl results CLN2 disease Iwan etal. UCL data repository. 2021."
}
|
[
{
"id": "90536",
"date": "11 Aug 2021",
"name": "Michel Boutin",
"expertise": [
"Reviewer Expertise I have a Ph.D. in chemistry and I performed postdoctoral trainings in proteomics and metabolomics. Since 2011",
"I am the technical director of the Waters-CHUS Expertise Centre in Clinical Mass Spectrometry (Sherbrooke",
"QC",
"Canada). My main area of research concerns the discovery of biomarkers for rare genetic diseases using untargeted metabolomics."
],
"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 this brief report have tested the possibility to use the neurofilament light chain (NfL) levels in cerebrospinal fluid as a biomarker to monitor the response to cerliponase alfa for patients suffering from CLN2, the classic late infantile neuronal ceroid lipofuscinosis. The biomarkers were analysed in specimens of six patients at the initiation of treatment and followed up from 14-84 days after, and for six other patients from 9-10 months to 2.5 yrs post-treatment. Since CLN2 is an extremely rare genetic disease, I think that it was a major accomplishment to longitudinally monitor the biomarkers for a cohort of 12 patients. The results obtained revealed a statistically significant long-term decrease of NfL levels in cerebrospinal fluid of CLN2 patients treated with cerliponase alfa. However, soon after the initiation of ERT (≤ 84 days), the biomarker levels increased for some patients and decreased for others. It suggests that the NfL levels might be used to adjust patient regimen, but further studies will be needed to confirm it. Moreover, we must keep in mind that NfL is a non-specific marker of neuroinflammation, and its level is also affected by repeat surgeries and infections due to the intracerebroventricular device used to dispense the enzyme replacement therapy.\nMinor revisions:\n\nIn the title, I suggest adding “chain” between “light” and “levels”.\n\nIn the second paragraph of the “Samples” section, I suggest adding the limit of detection and the limit of quantification of the Simoa kit, as well as the concentration of the internal quality control sample.\n\nIn the “Analysis section”, I suggest replacing “Results were exported to Microsoft Excel15” with “Results were downloaded in the UCL data repository15”\nI think that it can be less confusing for the reader if the patients are labeled 1 to 12, instead of 1480, 1479, 1488, 330 … in the figures, the table, and in the core of the manuscript.\n\nIn the \"Results and Discussion\" section, second paragraph, first line: Please replace (n = 5) by (n = 6).\n\nFor Figures 1 and 2, the shape of the data point marks might be changed for the different patients (Ex: square, triangle ...) to facilitate the comprehension of the graphs when the article is printed in black and white.\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? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7538",
"date": "05 Jan 2022",
"name": "Wendy Heywood",
"role": "Author Response",
"response": "Many thanks. All the recommended changes have been made to the manuscript."
}
]
},
{
"id": "96195",
"date": "09 Nov 2021",
"name": "Daniel Erskine",
"expertise": [
"Reviewer Expertise Neurodegenerative disease pathology",
"neurometabolic disease pathology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript, by Iwan and colleagues, set out to longitudinally follow patients with the CLN2 form of Neuronal Ceroid Lipofuscinosis, to detect response to enzyme replacement therapy by evaluating CSF levels of NfL. There is a pressing need to better evaluate response to treatment in CLN2 patients receiving enzyme replacement therapy, as current measures are limited to clinical instruments. Whilst clinical scales are useful to show functional improvement, clinical features likely follow from progressive degeneration over time, and thus may lack the sensitivity to detect changes in neurodegeneration. Evaluation of NfL levels in CSF has been gaining traction as a relatively broad measure of axonal degeneration across a range of neurodegenerative conditions, and the authors quite reasonably suggest this may be a more sensitive measure of treatment response compared to clinical tests alone. NfL levels were measured in CSF using the highly sensitive SIMOA platform that is optimised for detecting even low levels of the analyte of interest. They identified a reduction in NfL over time in most cases following enzyme replacement therapy, but this was often 2-3 years following treatment initiation. The authors note the variability in response and discuss the potential of using this information to monitor treatment response and potentially adjust regimens.\nOverall, I thought this was an excellent manuscript. Given the rarity of CLN2 and the longitudinal nature of this study, the number of participants was particularly impressive. I have some suggestions for the authors to consider:\nI felt there was a lack of relationship with clinical variables. Given that the stated aim of the study was to augment current monitoring with CLN2 CRS, I was surprised to see no attempt at associating changes in CLN2 CRS with NfL levels over time.\n\nWas any imaging performed to corroborate the suggestion that changes in NfL are associated with reduced axonal degeneration or neurodegeneration?\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? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7539",
"date": "05 Jan 2022",
"name": "Wendy Heywood",
"role": "Author Response",
"response": "Many thanks for reviewing the report. We tried to analyse whether the speed of loss of points on CLN2 clinical score is correlated with the slope of NFL normalisation, i.e. whether NFL levels can act as a biomarker of response to enzyme replacement therapy (ERT). We did indeed look at this and did not find a statistically significant correlation. This could be due to a few factors such as the small number of patients in the study, the fact that CLN2 score is not sufficiently sensitive to detect small changes in response or there is no real correlation between the NFL levels and the patients response to ERT. In response ot your other question the MRI scans are performed yearly in the patients which is similar to the clinical trial previously reported by Schulz et al. NEJM 2018, where MRI grey matter volume changes was one of the outcome measures. The results in our patients were in line with the clinical trial report where patients lost approximately 10.5% of total grey matter volume in the first year of treatment and 3.3%in the second year which indeed indicates neurodegenerative processes."
}
]
}
] | 1
|
https://f1000research.com/articles/10-614
|
https://f1000research.com/articles/9-1159/v1
|
21 Sep 20
|
{
"type": "Method Article",
"title": "Space-log: a novel approach to inferring gene-gene net-works using SPACE model with log penalty",
"authors": [
"Qian (Vicky) Wu",
"Wei Sun",
"Li Hsu",
"Wei Sun"
],
"abstract": "Gene expression data have been used to infer gene-gene networks (GGN) where an edge between two genes implies the conditional dependence of these two genes given all the other genes. Such gene-gene networks are of-ten referred to as gene regulatory networks since it may reveal expression regulation. Most of existing methods for identifying GGN employ penalized regression with L1 (lasso), L2 (ridge), or elastic net penalty, which spans the range of L1 to L2 penalty. However, for high dimensional gene expression data, a penalty that spans the range of L0 and L1 penalty, such as the log penalty, is often needed for variable selection consistency. Thus, we develop a novel method that em-ploys log penalty within the framework of an earlier network identification method space (Sparse PArtial Correlation Estimation), and implement it into a R package space-log. We show that the space-log is computationally efficient (source code implemented in C), and has good performance comparing with other methods, particularly for networks with hubs.Space-log is open source and available at GitHub, https://github.com/wuqian77/SpaceLog",
"keywords": [
"Gene-gene network",
"gene regulation",
"penalized regression",
"log penalty",
"partial correlation",
"R package",
"algorithm"
],
"content": "Introduction\n\nThe objective of this paper is to introduce a novel method that constructs gene-gene network (GGN) based on high dimensional gene expression data. Popular methods for GGN include neighborhood selection1, graphical Lasso2, and space (Sparse PArtial Correlation Estimation)3. Neighborhood selection consistently estimates the non-zero entries of the partial correlation matrix, and provide an approximation of the maximum likelihood estimate of partial correlation matrix. Graphical Lasso improves on neighborhood selection by providing a maximum likelihood estimate of the partial correlation matrix. The space method exploits the symmetry of partial correlation matrix to improve the estimation accuracy. It also avoids potential conflicts in neighborhood selection, that is, Yi is selected as a neighbor of Yj but Yj is not selected as a neighbor of Yi, and one has to make a post-hoc decision for whether Yi and Yj are connected. Furthermore, those available methods employ L1, L2 or elastic net penalty. However, penalties in the range of L0 to L1 is often needed to improve the accuracy of variable selection for high-dimensional gene expression data4. In this paper, we propose a new statistical method to estimate GGN by implementing the log penalty for the space approach, and we refer to our method as space-log.\n\n\nMethods\n\nSuppose that we have data on n independent individuals and m genes. Assume the expression of m genes, after appropriate normalization, follow a multivariate Gaussian distribution N(0, ∑).\n\nThe neighborhood selection (NS) approach considers each gene separately. Let Yi be the gene expression value for the ith gene and Y−i = (Y1, ..., Yi−1, Yi+1, Ym)T . For the NS approach, Yi is regressed on Yi by a penalized regression:\n\n\n\nwith penalty function p(|β|;ω). We will compare NS-lasso with lasso penalty p(|β|;λ)=λ|β|5 and NS-log with log penalty p(|β|;λ,τ)=λlog(|β|+τ)6,7. Source codes of NS-lasso and NS-log are available at https://github.com/Sun-lab/penalized_estimation/.\n\nThe joint modeling approach space3 is to estimate GGN, without the need to fit many (m) single gene regression models separately, but directly estimate partial correlation among all the genes. Denote the partial correlation between Yi and Yj by ρi,j. If we know the concentration matrix ∑−1 = (σij)m×m, then ρi,j=−σijσiiσjj. So we can easily get that ρi,j=sign(βi,j)βijβji. Thus, the problem is translated into partial correlation matrix estimation. Specifically3, proposed to minimize a penalized loss function\n\n\n\n\n\nwhere wi ≥ 0 is the weight, e.g., uniform weights wi = 1 for space-no, residual variance based weights wi = σjj for space-res, and degree based weights wi = number of genes that {j : ρi,j ≠ 0, j ≠ i} for space-df. In 3, p(|ρ|; λ) = λ|ρ| and we call it as space-lasso.\n\nInspired by 6 and 7, we extended the space approach with log penalty as space-log p(|ρ|; λ, τ) = λlog(|ρ| + τ) and used the active shooting algorithm3 to update the coefficient estimates iteratively in space-log (Extended data). We determined the tuning parameters by using extended BIC (extBIC)8.\n\nDenote the target loss function as\n\n\n\nThe goal is to estimate ρ^ = argminρf(ρ) for a given λ and τ. We implement the penalized estimation using space and Log penalties by Local Linear Approximation (LLA)9.\n\n\n\nWhere |ρ^i,j(k)| is the estimate of regression coefficient ρi,j at the k-th iteration. After applying LLA for the penalty part, we can minimize loss function at the (k + 1)-th step, while solving for ρi,j by\n\n\n\nBy letting ∂f(k+1)(ρi,j)/∂ρi,j=0, we can find the solution for ρi,j as follows:\n\nwhere zi,j(k)=Yj(Yi−∑l≠i;l≠jρ^i,l(k)σ^(k)llσ^(k)iiYl)/vj,vj=YjTYj, and p′(|ρ^i,j(k)|;λ,τ)=sgn(ρ^i,j(k))λ|ρ^i,j(k)|+τ.\n\nWe adapted the same idea active-shooting algorithm from3 to update the coefficient estimation iteratively in space-log. Without loss of generality, we kept most notation from3 but tailored with space-log. The details are included in the Extended data.\n\n\nSimulation studies\n\nIn this section, we present Monte Carlo simulation to evaluate the performance of the space-log, space-lasso, NS-log, and NS-lasso. Following7, we studied two types of graphs: the traditional random graphs (ER model) where all the genes have the same expected number of neighbors10,11, and hubs graphs where a few genes may have a large number of neighbors (BA model), and BA model is more frequently observed in gene networks12.\n\nWe simulated GGN of m genes under both the BA and ER models, respectively. The initial graph had one gene and no edge. In the (k+1)th step, we added e edges between a new gene and e old genes. Under the BA model, there is a greater probability for the new gene to connect to an existing hub gene that has larger number of edges with the probability pE=vi(t)/∑jvj(t), where vj(t) number of edges connected with the ith gene at the tth step. For the ER model, each edge of any gene pair (Gi,Gj) was added randomly in the GGN with probability pE independent from all other edges. After constructing the bone of GGN, we simulated gene expression based on multivariate Gaussian. Without loss of generality, we simulated data sets with n = 400 individuals. As shown in Table 1, we considered different number of genes m = 100, 200, 300 with various sparsity level determined by pE = 1=m or 2=m for the ER model and e = 1 or e = 2 for the BA model.\n\nWe evaluated the performance of the methods by the following metrics: number of false positives (FP), false negatives (FN), FP+FN, F1 score, FDR, true positive rate (power). Note that there are three different weights used in joint modeling setting (space-log, space-lasso): (1) uniform weights; (2) residual variance based weights; and (3) degree freedom based weights. The corresponding methods are referred to as sp_no, sp_res, and sp_df with/without log respectively.\n\nUnder the BA model with m=100 and e=1 (Figure 1), we can see that space-log has smallest Errors (FP+FN), smallest FDR, and highest F1 score than other approaches, indicating that space-log controls overall false positive and false negative rates well. Under the ER model (Figure 2) with m=100 and e=1, space-log is slightly better than space, and NS-log shows lower Errors and higher F1 score than other approaches including space-log. Under both models, the log penalty has less false positives but slightly more false negatives compared to lasso penalty. We note that although log penalty performs well for both the ER and BA models, space-log is particularly powerful in identifying hub networks (such as BA models).\n\nIn the Extended data, Figures S3 and S4 show the results under the BA model for m=100,200,300 with low number of connections (e=1) and high number of connections (e=2), respectively. Figures S5 and S6 show the results under the ER model with low and high numbers of connections, respectively. Comparing with Figure 1, a similar pattern was noted with the increase of number of genes (m increases from 100, 200, to 300). In BA with low connections (Figure S3), space-log showed smallest FP+FN error and largest F1 score, which outperform all other methods. In BA with high connections (Figure S4), NS-log showed smallest FP+FN error and largest F1 score. For ER model with low and high connections, NS-log outperforms other methods in terms of FP+FN and F1 scores. It’s in line with our understanding that space-log is powerful at identifying hubs network, and NS-log is powerful at dealing with complex network with high number of gene-gene interactions and random networks.\n\nWe showed a simulated graph for the BA model with 400 subjects, 100 genes and each gene has only 1 connection (Figure 3). The GGN was estimated by 8 different approaches. In Figure 3, the true edges were indicated by black color, false positive (FP) edges by red color, and false negative (FN) edges by grey color. It’s clear that space-log identified far fewer false positive edges (red line) comparing with space-lasso and NS approaches, while clearly indicating the hub structures. We observed that the FP edges by two NS approaches were quite randomly identified, and the FP edges by two space approaches were mostly within a hub and not between hubs. In summary, the log penalty generally has better performance than the lasso penalty, and both space-log and NS-log control false positive and false negative rate well. For random networks, i.e., no hub, NS-log performs better than other methods. space-log performs best for hub-like gene networks (Figure 1 and Figure 3) with higher F1 score and less false positive edges. Identifying hub networks is generally considered of great interest in the GGN analysis, because a few of hubs connecting with a large proportion of genes, and those hub genes are thought to be master regulators and play a critical role in a biological system13.\n\nA total of 400 subjects were generated. The GGN was estimated by 8 different approaches. Black is true edges, red is false positive edges, and grey is false negative edges.\n\n\nApplication to GTEx and TCGA data\n\nWe applied both proposed space-log and existing methods (space-lasso, NS-log, and NS-lasso) to identify GGN using RNA-seq data from tumor tissue of 550 TCGA (The Cancer Genome Atlas) Colon Adenocarcinoma (TCGA-COAD) cancer patients14. The preprocessing steps of RNA-seq data included: (1) transforming the expression of each gene by log(total read count) = logTReC (2) removing the confounding effects by taking residuals of logTReC from a linear regression with the following covariates: 75% of logTReC per sample (which captures read depth), plate, institution, age, and six PCs from the corresponding germline genotype data. After removing genes with low expression across most samples, we had 18,238 genes and 450 samples.\n\nWe considered gene sets C6 curated oncogenic pathways by MSigDB from the Broad Institute and inferred the GGN within each gene set. There were 189 gene pathways with a total of 8,737 unique genes for which TCGA have expression data. The sizes of gene sets ranged from 9 to 338 genes. Since we don’t know the true GGN, we downloaded the common pathway version 10 from www.pathwaycommons.org to provide a partial \"gold standard\". The observed GGN by different methods were compared with the known edges from common pathway and calculated FP, FN, FP+FN, number of total discovery, F1 score, and true positive rate (Extended data: Figure S10). The NS-based approach with both LASSO and log penalty discovered much more edges than space-based approach and space-log had fewer false positive (fewer FN+FP too) than space-lasso. There is almost no difference on number of false negative between different methods, as well as F1 score (Figure 4). Furthermore, in order to show the performance of these methods on the hub networks, we identified 17 pathways with hub-like genes (each hub gene set has < 50 genes and variance of the number of identified edges for each gene in the gene set > the first quartile of all 189 gene sets) and re-calculated the summary metrics in Figure 5. We noted that space-log approach has smallest Errors and slightly higher F1 than other approaches, which is in line with our finding in simulation that space-log is powerful in identifying hub networks, (such as BA models).\n\nThe Genotype Tissue Expression (GTEx) project15 aims to study tissue-specific gene expression and regulation in normal individuals. In this paper, we used gene expression data (RNA-seq) from blood tissue of 451 patients to identify GGN. We pre-processed gene expression data using the same procedure as for TCGA data. We mapped genes to gene pathways by MSigDB (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). A total of 189 gene pathways were represented with a total of 8097 unique genes. The size of gene sets ranged from 8 to 306 genes.\n\nAgain, we applied space-log, space-lasso, NS-log, and NS-lasso approaches to identify GGN. Using the same common pathway file used for the TCGA analysis as gold standard, we calculated FP, FN, FP+FN, # of discovery, F1, TPR (Figure 6). We obtained very similar results to the TCGA data. The NS-based approach with both LASSO and log penalty discovered much more edges than the space-based approach and space-log has fewer false positive (fewer FN+FP too) than space-lasso. There is almost no difference in the number of false negative between different methods, as well as F1 score. A similar sensitivity analysis was conducted to a subset of hub-type genes (Figure 7), where 30 pathways were selected to be in the first quartile of the variance of the number of identified genes with < 50. It also showed the space-log approach has smallest Errors (F1 is similar to other approaches).\n\n\nConclusions\n\nIn this paper, we proposed a new joint modeling method with log penalty, space-log, to identify gene-gene network. An assumption of the GGN analysis is that most of gene pairs do not directly interact with each other, and there are a few of master genes (hubs) for network that connect with many other genes, which are thought to play a critical role in a biological system13,16. Both simulation and real data analyses showed that space-log is particularly powerful in identifying hub networks and master genes, which is considered of great interest in gene-gene network analysis. In the Extended data, we compared several tuning parameter selection approaches, such as BIC Zou et al.17, extBIC8,18, and oracle4, and showed that extBIC outperforms other methods in simulation. The R package \"SpaceLog\" on GitHub includes algorithms, simulation, and real data examples: https://github.com/wuqian77/SpaceLog.\n\n\nData availability\n\nSimulation data. We used barabasi.game function from igraph R package to generate the skeleton of a BA model.\n\nSource code, simulated data, and plots: https://github.com/wuqian77/SpaceLog/tree/master/Simulation.\n\nTCGA data. The RNA-seq dataset from tumor tissue of 550 TCGA (The Cancer Genome Atlas) colon adenocarcinoma (TCGA-COAD) cancer patients14 can be downloaded from dbGap phs000178.v1.p1.: https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga.\n\nPre-processing and data analysis source code: https://github.com/wuqian77/SpaceLog/tree/ master/Analysis/TCGA.\n\nGTex data. The RNA-seq dataset of blood tissue from the Genotype Tissue Expression (GTEx) project15 can be downloaded from dbGap Genotype-Tissue Expression Project and the study accession is phs000424.v7.p2.: https://www.gtexportal.org/home/datasets.\n\nPre-processing and data analysis source code: https://github.com/wuqian77/SpaceLog/tree/master/Analysis/GTex.\n\nZenodo: SpaceLog: First release of spacelog, http://doi.org/10.5281/zenodo.400293119.\n\nThis project contains the following extended data:\n\nthe detailed algorithm for active shooting;\n\nsimulation and figures on comparing methods to choose tuning parameters;\n\nsimulation and figures on comparing different GGN methods under various scenarios.\n\nLicense: GPL-3\n\n\nSoftware availability\n\nSource code for space-log available from: https://github.com/wuqian77/SpaceLog\n\nArchived source code as at time of publication: http://doi.org/10.5281/zenodo.400293119.\n\nLicense: GPL-3\n\nSource code for NS-log and NS-lasso available from: https://github.com/Sun-lab/penalized_estimation\n\nLicense: GPL-3\n\nExisting methods space-lasso is available on R CRAN: https://cran.r-project.org/web/packages/space/index.html.",
"appendix": "References\n\nMeinshausen N, Bühlmann P, et al.: High-dimensional graphs and variable selection with the lasso. The annals of statistics. 2006; 34(3): 1436–1462. Publisher Full Text\n\nFriedman J, Hastie T, Tibshirani R: Sparse inverse covariance estimation with the graphical lasso. Biostatistics. 2008; 9(3): 432–441. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPeng J, Wang P, Zhou N, et al.: Partial correlation estimation by joint sparse regression models. J Am Stat Assoc. 2009; 104(486): 735–746. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen TH, Sun W, Fine JP: Designing penalty functions in high dimensional problems: The role of tuning parameters. Electron J Stat. 2016; 10(2): 2312–2328. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTibshirani R: Regression shrinkage and selection via the lasso. J R Statist Soc B. 1996; 58: 267–288. Reference Source\n\nSun W, Ibrahim JG, Zou F: Genomewide multiple-loci mapping in experimental crosses by iterative adaptive penalized regression. Genetics. 2010; 185(1): 349–359. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHa MJ, Sun W, Xie J: Penpc: A two-step approach to estimate the skeletons of high-dimensional directed acyclic graphs. Biometrics. 2016; 72(1): 146–155. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen J, Chen Z: Extended bayesian information criteria for model selection with large model spaces. Biometrika. 2008; 95(3): 759–771. Publisher Full Text\n\nZou H, Li R: One-step sparse estimates in nonconcave penalized likelihood models. Ann Stat. 2008; 36(4): 1509–1533. PubMed Abstract | Publisher Full Text | Free Full Text\n\nErd˝os-A Rényi P, Erdos P: On the evolution of random graphs. Publ Math Inst Hung Acad Sci A. 1960; 5: 17–61. Reference Source\n\nKalisch M, Bühlmann P: Estimating high-dimensional directed acyclic graphs with the pc-algorithm. J Mach Learn Res. 2007; 8(Mar): 613–636. Reference Source\n\nBarabási AL, Albert R: Emergence of scaling in random networks. Science. 1999; 286(5439): 509–512. PubMed Abstract | Publisher Full Text\n\nBarabasi AL, Oltvai ZN: Network biology: understanding the cell’s functional organization. Nat Rev Genet. 2004; 5(2): 101–13. PubMed Abstract | Publisher Full Text\n\nGenome C, Network A, et al.: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407): 330–337. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAguet F, Brown AA, Castel S, et al.: Local genetic effects on gene expression across 44 human tissues. BiorXiv. 2016; 074450. Publisher Full Text\n\nLiu Z, Meng J, Li X, et al.: Identification of hub genes and key pathways associated with two subtypes of diffuse large b-cell lymphoma based on gene expression profiling via integrated bioinformatics. Biomed Res Int. 2018; 2018: 3574534. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZou H, Hastie T, Tibshirani R, et al.: On the “degrees of freedom” of the lasso. The Annals of Statistics. 2007; 35(5): 2173–2192. Publisher Full Text\n\nChen J, Chen Z: Extended bic for small-n-large-p sparse glm. Statistica Sinica. 2012; 555–574. Publisher Full Text\n\nwuqian77: wuqian77/SpaceLog: First release of spacelog (Version v.1.0.1). Zenodo. 2020. http://www.doi.org/10.5281/zenodo.4002931"
}
|
[
{
"id": "71868",
"date": "14 Oct 2020",
"name": "Yuying Xie",
"expertise": [
"Reviewer Expertise Statistics",
"Biostatistics",
"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 paper introduces an extension of the SPACE (Sparse Partial Correlation Estimation) method, which is used to estimate a gene-gene network (GNN). The proposed framework, space-log, relies on the log penalty, which delivers better variable selection performance than LASSO, especially for GGN with hubs. The authors also have created a very efficient R package for the proposed method. The paper is clearly written, and the proposed method showed promising results for real data analyses. I list my questions below:\nIn both TCGA and GTEx analyses, the dimensions m is smaller than the sample size n. Since log penalty can handle high dimension low sample size data, can you also include a real application with m larger than n?\n\nThe numerical results are all based on the tuned model using extended BIC, which is one-shot of the result. It is better to also include ROC curves reflecting the whole spectrum of the results for a range of tuning parameters.\n\nMinor comments:\nIn formula (3), the ‘square root’ should not include Yj.\n\nIn t page 3 section ‘Joint modeling space using lasso penalty: space-lasso’, it is better to include the relationship between \\beta_{ij} and \\simga_{ij} before making the conclusion that \\rho_{i,j} = sign(\\beta_{i,j}) \\sqrt{\\beta{ij}\\beta_{ji}}.\n\nFor the log penalty, please also cite ‘Enhancing sparsity by reweighted L1 minimization’.\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? Yes",
"responses": [
{
"c_id": "7558",
"date": "05 Jan 2022",
"name": "Qian Wu",
"role": "Author Response",
"response": "In both TCGA and GTEx analyses, the dimensions m is smaller than the sample size n. Since log penalty can handle high dimension low sample size data, can you also include a real application with m larger than n? We thank the reviewer for pointing out this limitation. We “create” some larger network by combining some gene sets with overlapping genes (m > n). An updated “larger size network” graph is added in supplementary. https://github.com/wuqian77/SpaceLog/blob/master/Document/F1000Research_Journal_Article_Spacelog_Supplementary_Materials.pdf The numerical results are all based on the tuned model using extended BIC, which is one-shot of the result. It is better to also include ROC curves reflecting the whole spectrum of the results for a range of tuning parameters. Good comment. Cross-validation (CV) approach is commonly used to choose the tuning parameter but time-consuming, and recent literature (Wang et al., 2009) showed BIC-type approach has better performance than CV. Thus, we tried different tuning parameters and used grid search to generate an “Oracle” result (based on maximize F1 score or minimize FDR) in supplementary (section S2.3). It showed extBIC performs better than BIC and its performance is close to Oracle for space approach. https://github.com/wuqian77/SpaceLog/blob/master/Document/F1000Research_Journal_Article_Spacelog_Supplementary_Materials.pdf Minor comments: In formula (3), the ‘square root’ should not include Yj. In t page 3 section ‘Joint modeling space using lasso penalty: space-lasso’, it is better to include the relationship between \\beta_{ij} and \\simga_{ij} before making the conclusion that \\rho_{i,j} = sign(\\beta_{i,j}) \\sqrt{\\beta{ij}\\beta_{ji}}. For the log penalty, please also cite ‘Enhancing sparsity by reweighted L1 minimization’. We thank the reviewer for pointing out this oversight. We have updated the manuscript accordingly."
}
]
},
{
"id": "71864",
"date": "19 Oct 2020",
"name": "Chi Song",
"expertise": [
"Reviewer Expertise Biostatistics",
"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\nIn this paper, the authors developed “space-log”, a new method to infer gene-gene network (GGN), by incorporating log penalty into the “space” method. The authors compared their method to the original “space” with LASSO penalty and the neighborhood selection (NS) methods, using simulation and real data. In general, the description of the proposed method is clear, and the simulation and real application settings made sense. However, I believe this paper needs to be revised to (1) provide the rationale for choosing the combination of “space” and log penalty, (2) compare with more state-of-the-art methods, and (3) improve the presentation and writing. Here are some specific comments.\nThe authors need to discuss why they decided to combine “space” and log penalty for GGN detection. What is the benefit of using log penalty over other penalty choices, including concave penalties and other nonconcave penalties such as SCAD, MCP, and TLP? The introduction should be extended to include more state-of-the-art methods, such as adaptive LASSO or high-dimensional regression methods with sparse precision matrix estimation.\n\nAlthough briefly mentioned gLasso in the introduction, the authors did not talk about this class of methods in the rest of the paper. I am curious to see how space-log compares to gLasso and its extensions with nonconcave penalties in simulation and real application (see Fan et al., 2009). 1\n\nBased on my understanding, the major benefit of using nonconcave penalties is to reduce the estimation bias of the correlation coefficients. I suggest the authors include comparisons based on the coefficient estimation. In addition, the authors should provide details about how the precision matrices are simulated. Currently, only the simulation methods for its bone structure are provided.\n\nIn conclusion/discussion, the authors should provide more insights or heuristics about why the proposed method performed better than other methods. What aspects of the data makes the proposed method favorable? Is there any limitation that the users should pay attention to when applying this method in application?\n\nMinor comments:\nThe citations in this paper are apparently converted from an author-year citation format. The authors need to make changes to the writing to adapt to numbered citation format.\n\nPresentation and writing issues, for example:\n\nThe authors need to decide if a comma is needed between two subscripts in the notation (e.g. \\beta_{ij} or \\beta_{i,j} on page 3 left column). On page 4, left column, third paragraph, the sentence “The initial paragraph …” only applies to BA model, but not ER model. Also, it should be “in the (t+1)th step” instead of “in the (k+1)th step”. In the last sentence of this paragraph, it should be “1/m” and “2/m”. This is not an exhaustive list of writing issues. I suggest the authors proofread carefully.\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? Partly\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "86957",
"date": "21 Jun 2021",
"name": "Jessie Jeng",
"expertise": [
"Reviewer Expertise Statistics",
"Statistical 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\nThis paper considers the problem of identifying gene regulatory networks based on high-dimensional gene expression data. A new method, space-log, is introduced to perform penalized regression with a log penalty. The new method is compared with several existing methods in simulation and real applications using GTEx and TCGA data. The new method seems to outperform other methods in identifying networks with hubs and master genes.\n\nThe overall presentation is clear. However, several improvements can be made:\nI think it would be important to explain why the proposed method has advantages in identifying networks with hubs. I would imagine that a network with hubs tends to have more diverse sparsity levels of association across different genes than a network without hubs. Is the proposed method with a log penalty more effective for such scenarios? Or there are other reasons?\n\nThe Introduction is a bit too short. I would suggest adding more biological background and a motivation from a real application point of view.\n\nSome discussions on the computational complexity or a comparison of the computational times of different methods should be helpful.\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? Partly",
"responses": [
{
"c_id": "7529",
"date": "05 Jan 2022",
"name": "Qian Wu",
"role": "Author Response",
"response": "1. I think it would be important to explain why the proposed method has advantages in identifying networks with hubs. I would imagine that a network with hubs tends to have more diverse sparsity levels of association across different genes than a network without hubs. Is the proposed method with a log penalty more effective for such scenarios? Or there are other reasons? We totally agree with the reviewer that hub type network has more diverse sparsity (BA type graph has a larger variation (number of edges per gene) than ER type graph) and one additional evidence that log penalty works better for diverse sparsity are the results of an earlier paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628772/ e.g., the results in tables 1 and 2. 2. The Introduction is a bit too short. I would suggest adding more biological background and motivation from a real application point of view. Good comment. We added biological background in the introduction section accordingly. 3. Some discussions on the computational complexity or a comparison of the computational times of different methods should be helpful. We thank the reviewer for pointing out this. We have added the run-time discussion with a table in the online manuscript, and a figure in Supplementary Materials on Github. https://github.com/wuqian77/SpaceLog/blob/master/Document/F1000Research_Journal_Article_Spacelog_Supplementary_Materials.pdf"
}
]
}
] | 1
|
https://f1000research.com/articles/9-1159
|
https://f1000research.com/articles/11-5/v1
|
05 Jan 22
|
{
"type": "Systematic Review",
"title": "Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: a meta-analysis of 229 studies covering over 10M patients",
"authors": [
"Bart G. Pijls",
"Shahab Jolani",
"Anique Atherley",
"Janna I.R. Dijkstra",
"Gregor H.L. Franssen",
"Stevie Hendriks",
"Evan Yi-Wen Yu",
"Saurabh Zalpuri",
"Anke Richters",
"Maurice P. Zeegers",
"Shahab Jolani",
"Anique Atherley",
"Janna I.R. Dijkstra",
"Gregor H.L. Franssen",
"Stevie Hendriks",
"Evan Yi-Wen Yu",
"Saurabh Zalpuri",
"Anke Richters",
"Maurice P. Zeegers"
],
"abstract": "Background: This review aims to investigate the association of sex with the risk of multiple COVID-19 health outcomes, ranging from infection to death. Methods: Pubmed and Embase were searched through September 2020. We considered studies reporting sex and coronavirus disease 2019 (COVID-19) outcomes. Qualitative and quantitative data were extracted using standardised electronic data extraction forms with the assessment of Newcastle Ottawa Scale for risk of bias. Pooled trends in infection, hospitalization, severity, intensive care unit (ICU) admission and death rate were calculated separately for men and women and subsequently random-effects meta-analyses on relative risks (RR) for sex was performed. Results: Of 10,160 titles, 229 studies comprising 10,417,452 patients were included in the analyses. Methodological quality of the included studies was high (6.9 out of 9). Men had a higher risk for infection with COVID-19 than women (RR = 1.14, 95%CI: 1.07 to 1.21). When infected, they also had a higher risk for hospitalization (RR = 1.33, 95%CI: 1.27 to 1.41), higher risk for severe COVID-19 (RR = 1.22, 95%CI: 1.17 to 1.27), higher need for Intensive Care (RR = 1.41, 95%CI: 1.28 to 1.55), and higher risk of death (RR = 1.35, 95%CI: 1.28 to 1.43). Within the period studied, the RR for infection and severity increased for men compared to women, while the RR for mortality decreased for men compared to women. Conclusions: Meta-analyses on 229 studies comprising over 10 million patients showed that men have a higher risk for COVID-19 infection, hospitalization, disease severity, ICU admission and death. The relative risks of infection, disease severity and death for men versus women showed temporal trends with lower relative risks for infection and severity of disease and higher relative risk for death at the beginning of the pandemic compared to the end of our inclusion period. PROSPERO registration: CRD42020180085 (20/04/2020)",
"keywords": [
"COVID-19",
"sex-differences",
"male",
"femal",
"mortality",
"ICU admission",
"infection",
"severity"
],
"content": "Introduction\n\nThe role of sex has been a topic of interest in many coronavirus disease 2019 (COVID-19) studies, with many countries reporting higher case fatality rates among men than women1. There is, however, considerable variability among estimated effects of sex across countries for several relevant COVID-19 outcomes, including death. A recent systematic review from our group summarized literature from the earliest pandemic phase to show the impact of age and sex on commonly reported COVID-19 related outcomes2. We showed that men were observed to have a higher risk of confirmed COVID-19 infection among those tested, and more often had severe COVID-19 disease, required intensive care unit (ICU) admission and had a fatal outcome when hospitalized with COVID-192, a finding that other researchers3,4 have confirmed and has led to speculation on biological mechanisms5,6. However, almost all studies from previous systematic reviews were based on the early phase of the pandemic where testing was less commonly available, treatments were not yet evidence-based and mortality rates were high.\n\nThere are some indications that ICU and mortality rates have now decreased7–9, raising the question of whether men are still at increased risk in different severity stages ranging from infection to death now that substantially more data is available.\n\nHere we present a systematic review and meta-analysis on the association between sex and risk of COVID-19 for infection, hospitalization, disease severity, ICU admission and mortality. Studies in this review cover all continents with the exception of Antarctica, covering study populations from a large timeframe of the COVID-19 pandemic. This should provide a more nuanced insight into the association of sex with relevant COVID-19 outcomes and temporal variety of the association.\n\n\nMethods\n\nThe reporting of this systematic review and meta-analysis is in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement10 and a protocol has been registered a priori at the Prospero registry (CRD42020180085, 20th April 2020)11. The review aimed to quantify the relative risk of men versus women on five commonly reported COVID-19 related outcomes, specifically (see also Table 1): 1) confirmed COVID-19 infection among the general population; 2) hospitalization among patients with a confirmed COVID-19 infection; 3) severe (clinically/radiologically) COVID-19 among hospitalized patients with a confirmed COVID-19 infection; 4) ICU admission among hospitalized patients with a confirmed COVID-19 infection; and 5) death among hospitalized patients with a confirmed COVID-19 infection.\n\nCOVID-19=coronavirus disease 2019; ICU=intensive care unit.\n\nThe search strategy was devised with a specialised librarian (GF) and the following databases were searched from December 1st 2019 up to an including September 17th 2020: Medline via PubMed and EMBASE. We designed the search strategy to be sensitive and reproducible. The term COVID-19 was elaborated in combinations of controlled vocabulary and free text terms. See Appendix I in the Extended data12 for the full search strategy. Studies reported in languages spoken by the research team were eligible: English, Dutch, German, French, Spanish, and Russian.\n\nInitial screening on the basis of title and abstract of eligible studies was performed by allocating subsets of the search results to all members of the review team. When the information in the abstract did not suffice or where there was any doubt, the studies remained potentially eligible. The full text of potentially eligible studies was evaluated by a member of the review team (MZ, BP, AR, AA, JD, SH, EY and SZ). All records identified through the searches were collected in an electronic reference database and subjected to the following inclusion and exclusion criteria: the study had to focus on humans with COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections providing, or potentially providing, sufficient information to calculate relative risk for our pre-specified associations (Table 1). Studies were excluded when there was no data on controls, when the study focussed on a specific population (e.g., health care workers, paediatric patients), when the study quality score (see next paragraph) was less than 5 out of 9 and when patients were admitted to hospital for different indications than for COVID-19 (e.g., kidney transplant patients, patients with fractured bones).\n\nA reviewer team (MZ, BP, AR, AA, JD, SH, EY and SZ) from the review team extracted data from included studies regarding patient demographics, study characteristics, and the severity stages of COVID-19 including infection, hospitalization, severity, ICU admission, and death. To ensure data quality, a reviewer team (MZ, BP, AR, AA, JD, SH, EY and SZ) from the review team other than the one who initially included the paper, confirmed the inclusions and data extraction for 20 randomly selected papers. Additionally, one of the reviewers (AR) checked the inclusion and data extraction of all studies that were potential outliers in terms of absolute rate of the outcome or RR as visually identified on the forest plots. Risk of bias of the included studies was appraised using the Newcastle Ottawa Scale (NOS)13.\n\nWe used relative risks (RR) to assess the association between each severity stage (i.e., infection, hospitalization, severity, ICU admission, and death) and sex and performed a random-effects meta-analysis to determine the pooled effect sizes with corresponding 95% confidence intervals and 95% prediction intervals14. The amount of statistical heterogeneity was assessed through visual inspection of the forest plots and by calculating I² statistics15. If data allowed, we explored potential sources of statistical heterogeneity when I2 was above 40% (1) through subgroup analyses and (2) with random-effects meta-regression analyses on pre-defined factors, including geographical region, study quality, study size, days into the pandemic based on study start and end date, publication date, diagnostic modality (e.g., polymerase chain reaction [PCR] test, computerized tomography [CT] signs, clinical symptoms and their combinations that led to the diagnosis of COVID-19), and clinical setting (e.g., nursing home, home, hospital, general practitioner [GP] cohort).\n\nTo assess publication bias, we constructed funnel plots for visual inspection and statistically tested potential asymmetry using the Egger and Harbord test16,17. In case of asymmetry, a trim-and-fill method and cumulative meta-analyses was used to explore the magnitude and direction of publication bias.\n\nPatient and public involvement statement. This systematic review and meta-analysis is part of the World Health Organization (WHO) Evidence Collaborative on COVID-19 answering on of their rapid review priority questions on risk factors for infection and disease severity. Patients were not involved.\n\n\nResults\n\nThe literature search yielded 10,160 unique hits of which 614 studies were eligible after screening titles and abstracts. From these eligible studies, we excluded 444 studies: 8 focused on healthcare workers only, 19 were in languages not spoken by the research team; 26 were reviews; 49 had no data on controls; 2 had no data on cases; 6 scored below 5 on the New Castle Ottawa Scale; 71 did not report or evaluate sex differences; and 263 made no valid comparison between men and women. This left 170 studies and together with 59 studies from the previous systematic review the total number of included studies was 229 covering a total of 10,417,452 patients. Details of the study selection and included studies are given in Figure 1 (PRIMSA flow chart) and Appendix II in the Extended data12.\n\nOf the included studies, 94 were from China, 42 from the United States, 18 from Italy, 11 from the United Kingdom, 8 from South-Korea, 6 from Germany, 6 from Spain, 6 from Turkey, 4 from Brazil, 4 from Mexico, 3 from Denmark, 3 from Iran, 3 from Israel, 2 from Austria, 2 from India, 2 from Switzerland, 2 from Thailand, and 1 from each of the following countries: Argentina, Australia, Belgium, France, Honduras, Indonesia, Japan, Kuwait, Netherlands, Poland, Singapore, South Africa, and Sweden. Study size ranged from 21 to more than 8,000,000 individuals. The included studies recruited individuals in the period between December 1st 2019 and August 19th 2020. Data of individual studies, organized by exposure and outcome, are available as Underlying data.\n\nThe methodological quality of the included papers was relatively high with an average of 6.9 out of 9, as measured with the Newcastle Ottawa Scale (NOS). Details of NOS items for individual studies, organized by exposure and outcome are available as Underlying data.\n\nMeta-analyses of the primary outcomes for the risk factor sex revealed differences among men and women18. An overview of the pooled results from random-effects meta-analyses for the risk factor sex can be found in Table 2. There was an unambiguous association between each stage of disease severity and sex with men having a higher risk of infection, hospitalization, disease severity, ICU admission and death than women.\n\nRR = relative risk; 95% CI = 95% confidence interval; 95% PI = 95% prediction interval; ICU=intensive care unit.\n\n1. Risk of infection\n\nIn total, 41 studies conducted in the general population reported data on the risk of infection and sex (Table 2). Men were shown to have a higher risk of infection; the pooled RR from these studies was estimated to be 1.14 (95%CI: 1.07–1.21). Four studies from China, two studies from South Korea and United States each and one study from Thailand and United Kingdom each reported a higher risk of infection among women (see Figure appendix III in the Extended data12). In the sensitivity analysis, the study start date was significantly associated with the relative risk of infection: the later the start date of the study the higher the risk of infection for men compared to women (Figure 2).\n\nThe size of the circles is inversely proportional to the variance of the estimated treatment effect. The dashed lines represent the limits of the 95% confidence interval (CI).\n\n2. Hospitalisation\n\nOverall, 22 studies reported on hospitalisations among confirmed COVID-19 cases. When diagnosed, the risk of hospitalization was about 33% (Table 2) more for men as compared to women (RR: 1.33, 95%CI: 1.27 – 1.41), (Figure appendix III in the Extended data12)\n\n3. Disease severity\n\nIn total, 77 studies reported on disease severity among populations hospitalised due to COVID-19. When hospitalised, men experienced more severe disease than women (RR = 1.22, 95%CI: 1.17- 1.27) implying that the risk of severe disease of COVID-19 for men is 22% higher than that for women (Table 2, Figure appendix III in the Extended data12). In the sensitivity analysis, start date was significantly associated with the relative risk disease severity: the later the start date of the study the higher the risk of disease severity for men compared to women (Figure 3).\n\nThe size of the circles is inversely proportional to the variance of the estimated treatment effect. The dashed lines represent the limits of the 95% confidence interval (CI).\n\n4. ICU admittance\n\nIn total, 48 studies reported on ICU admittance among hospitalised COVID-19 cases. The rate of admission to ICU in COVID-19 hospitalised patients was higher among men as compared to women. The aggregated effect size was 1.41 with a 95%CI of 1.28–1.55 (Table 2, Figure appendix III in the Extended data12). In the sensitivity analysis, study duration was significantly associated with the relative risk of ICU admittance: the longer the duration of the study, the higher the relative risk of admission to ICU for men than women (Figure 4).\n\nThe size of the circles is inversely proportional to the variance of the estimated treatment effect. The dashed lines represent the limits of the 95% confidence interval (CI).\n\n5. Death\n\nOverall, 91 studies reported on death among hospitalized COVID-19 cases. We observed that men were at higher risk of death (Table 2, Figure appendix III in the Extended data12) from COVID-19 as compared to women (RR = 1.35, 95%CI: 1.28–1.43). In the sensitivity analysis, start date was significantly associated with the relative risk of death: the later the start date of the study the lower the risk of death for men compared to women (Figure 5).\n\nThe size of the circles is inversely proportional to the variance of the estimated treatment effect. The dashed lines represent the limits of the 95% confidence interval (CI).\n\n1. Overlap in study populations\n\nConsidering the vast number of studies on COVID-19 the potential effect of overlap of study populations on the results should be evaluated. In instances where two studies were from the same region, had similar or overlapping patient recruitment periods or same hospitals- one could suspect a possible overlap in the studied populations. We conducted a sensitivity analysis by only including the largest study from a group of studies with a possible study population overlap.\n\nOverall, the estimates from the meta-analysis were very robust and the results did not demonstrate any substantial shifts in pooled effect estimates for any of the five study outcomes after exclusion of studies with possible overlap (Table 3).\n\nStudies with possible overlap of patients were excluded from the analysis, results presented in bold. Possible overlap was assumed when studies were from the same region, recruitment period and hospital. In a group of studies with possible overlap only the largest study was included in the analysis. The estimates from the meta-analysis were very robust and did not demonstrate any substantial shifts in pooled effect estimates for any of the five study outcomes after exclusion of studies with possible overlap.\n\nRR = relative risk; ICU=intensive care unit.\n\n2. Heterogeneity\n\nIn our primary outcome analysis (Table 2), we observed moderate to substantial heterogeneity. To address this, we also performed extensive sensitivity analyses consisting of subgroup and meta-regression analyses (Appendix IV in the Extended data12). The conclusions of our study did not markedly change with subgroup analyses and meta-regression analyses.\n\n3. Publication bias\n\nFunnel plots showed some asymmetry for the relation between sex and the outcomes of severe disease and death (p-values of 0.000 and 0.030, respectively; Harbord test). Although the subsequent trim-and fill analysis revealed some reduction in the effect sizes, all conclusions remained the same. More specifically, the RR for severity changed from 1.22 to 1.19 and for death from 1.35 to 1.20.\n\n\nDiscussion\n\nIn this systematic review, we evaluated the association between sex and COVID-19 infection, hospitalization, disease severity, ICU admission and death based on studies from across the world. Our results showed that men were more likely to be affected or to be more severely affected by COVID-19 than women on all disease outcomes. Men appear to have a higher risk of COVID-19 infection (as compared to women). When infected, they were observed to have a higher risk of hospitalization, and when hospitalized they had higher risk of severe COVID-19 disease and ICU admission, and ultimately a higher risk of dying. We also observed that, within the time period studied, the relative risk of infection and severe disease increased for men compared to women, while the relative risk of mortality decreased for men compared to women. Additionally, the relative risk of ICU admission increased for men compared to women when the duration of the study increased, suggesting that focus on ICU admission should have sufficient follow-up.\n\nThe various hierarchical COVID-19 related outcomes were estimated among different populations, i.e. infection among the general population, hospitalization among people with confirmed infections, and severe disease, ICU admission and death among all hospitalized patients with COVID-19.\n\nWithin each of these domains, different mechanisms may be responsible for the observed associations of sex with these outcomes.\n\nThe risk of an individual for confirmed COVID-19 infection among the general population is the sum of several mechanisms, including the population spread in their area, their exposure to other people in occupational, leisure and social setting and the mitigating measures imposed by local government. These mechanisms are likely to play a different role across different geographical regions and the way they affect men and women differently. In some countries, working outside of the house with associated exposure is more equally divided between men and women than in other countries. The part of each sex in caring activities (e.g. child care or informal care for other family members) also likely varies between geographical regions and cultures. Indeed, we observed divergent risks that seem clustered within countries, most notably the higher risk of infection among women in two large studies in South Korea19,20. In South Korea, women were indeed over-represented in higher-risk professions i.e. among nurses, medical and welfare-related healthcare sectors; as well as social welfare-related sectors. Besides that, more women were employed in high-risk professions (like hairdressing, wedding service workers, household helpers, cooking attendants, educational professionals and related occupations)21. In addition, sexes show difference on attitude and behaviour facing COVID-19, in that women are more likely to perceive COVID-19 as a very serious health problem, to agree with restraining public policy measures, and to comply with them22–24. It, therefore, might cause men with more chances to be exposed to SARS-CoV-2. Most other countries show a consistently higher risk of men for COVID-19 infections, although the USA shows inconsistent estimates across studies. This may be related to the governing context where measures and work and care cultures vary considerably across different states. A sensitivity analysis on the timeframe of the study showed a trend towards increasing risk for men over time.\n\nThe risk of hospitalization when infected with COVID-19 should be interpreted within both the medical and health care context. First, there may be medical mechanisms in play that cause men and women to divergently develop COVID-19 severity that requires hospitalization. Indeed, other respiratory tract infections tend to be more severe in men25. However, hospital capacity was limited at times in some parts of the world due to peak admissions, possibly influencing the selection of patients that were admitted.\n\nThe risk of outcomes related to the severity of COVID-19 (i.e. severe disease, ICU admissions and death) among patients hospitalized for COVID-19 is considered to be more independent of societal context and relative risks of men compared to women should be interpreted as reflecting biological mechanisms. During the severe acute respiratory syndrome (SARS) epidemic of 2003 mortality was also higher in men26. Over the course of the COVID-19 pandemic, clinical care and treatment have improved due to increased knowledge on the clinical manifestations and course of disease. It seems that absolute risks of dying among hospitalized patients, both within each sex and overall, have decreased over time7–9.\n\nAll relative risks that have been presented in this meta-analysis are univariable associations between sex and COVID-19 outcomes. This means that, although men indeed experience higher rates on all outcomes (infection through death) in the real world, sex may not be the causal factor causing an increased risk at some outcomes. Instead, the observed associations may be the result of other causal factors which are unequally distributed between both sexes. Indeed, there is literature to support hypotheses of causal effects of comorbidities, weight distribution, and immunological characteristics. as mechanisms through which differences in outcomes are observed between sexes4–6,8.\n\nNevertheless, when researchers, clinicians and policymakers want to target the appropriate group for interventions (healthcare or vaccinations) or studies, these findings based on real-world data may be helpful in identifying sub-populations or important confounders. Additionally, they may play a role in hypotheses generation regarding causal mechanisms of COVID-19 outcomes.\n\nSome limitations of this study should be considered. In some studies on death, information on the subjects without an endpoint was missing, so there was a high risk of non-differential misclassification that could lead to bias\n\nAnother limitation is that although we have found that the RR for infection, disease severity and mortality changed during the course of the pandemic, our study is not designed to provide possible explanations. Future studies are required to explore possible mechanisms.\n\nOur review has the following strengths. Our search strategy was thorough and complete: we screened 10,160 individual records in addition to 11,550 hits of the previous paper on the first wave2. This meta-analysis includes papers based on worldwide and from various phases of the pandemic—from the first wave to the second wave before variants of concern were identified. Such variants of concern are likely to alter the overall absolute risk of several outcomes in this meta-analysis, and potentially affect relative risks of sexes for these outcomes as well. In the studies included, we have observed a large range of absolute risks as a result of studies from different phases of the pandemic and from various regions, to which the relative risk of sex seemed to be fairly robust. This is however not guaranteed for other strains and this possibility should be considered when we extrapolate these results to more recent settings.\n\nOur search strategy therefore ensured that the included studies cover a wide range of transmission-mitigation policies, cultures and clinical settings and that the included studies cover a mix of virus strains that are (clinically) similar in terms of transmissibility and disease severity. The methodological quality as reflected by the NOS score was high and a thorough sensitivity analysis could not refute the conclusions. The possible influence of publication bias was considered to be small as only small changes in effect size after the trim-and-fill analyses were observed.\n\n\nConclusion\n\nWe systematically reviewed the literature to determine the relation between sex as a risk factor for COVID-19 infection, hospitalisation, disease severity, ICU admission and death. Meta-analyses on 229 studies comprising 10 million patients showed that men have a higher risk for infection, hospitalisation, severe disease, ICU admission and death. Within the period studied, the relative risk for infection and severe disease increased for men compared to women, while the relative risk for mortality decreased for men compared to women.\n\n\nData availability\n\nHarvard dataverse: Replication Data for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients. https://doi.org/10.7910/DVN/DPP67G18.\n\nHarvard Dataverse: Appendix for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients. https://doi.org/10.7910/DVN/JPLKI912.\n\nHarvard Dataverse: PRISMA checklist for ‘Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: a meta-analysis of 229 studies covering over 10M patients’ https://doi.org/10.7910/DVN/TRIZJX10.\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\nTransparency declaration\n\nThe manuscript’s guarantors (BP, SJ and MZ) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.",
"appendix": "References\n\nDehingia N, Raj A: Sex differences in COVID-19 case fatality: do we know enough? Lancet Glob Health. 2021; 9(1): e14–e5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPijls BG, Jolani S, Atherley A, et al.: Demographic risk factors for COVID-19 infection, severity, ICU admission and death: a meta-analysis of 59 studies. BMJ Open. 2021; 11(1): e044640. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPeckham H, de Gruijter NM, Raine C, et al.: Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020; 11(1): 6317. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilliamson EJ, Walker AJ, Bhaskaran K, et al.: Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020; 584(7821): 430–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBwire GM: Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? SN Compr Clin Med. 2020; 1–3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGriffith DM, Sharma G, Holliday CS, et al.: Men and COVID-19: A Biopsychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions. Prev Chronic Dis. 2020; 17: E63. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLedford H: Why do COVID death rates seem to be falling? Nature. 2020; 587(7833): 190–2. PubMed Abstract | Publisher Full Text\n\nHorwitz LI, Jones SA, Cerfolio RJ, et al.: Trends in COVID-19 Risk-Adjusted Mortality Rates. J Hosp Med. 2021; 16(2): 90–2. PubMed Abstract | Publisher Full Text\n\nBoudourakis L, Uppal A: Decreased COVID-19 Mortality-A Cause for Optimism. JAMA Intern Med. 2021; 181(4): 478–479. PubMed Abstract | Publisher Full Text\n\nPijls B, Jolani S, Atherley A, et al.: PRISMA checklist for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients. Harvard Dataverse, V1. 2021. http://www.doi.org/10.7910/DVN/TRIZJX\n\nMoher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339: b2535. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPijls B, Jolani S, Atherley A, et al.: Appendix for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients. Harvard Dataverse, V1. 2021. http://www.doi.org/10.7910/DVN/JPLKI9\n\nWells G, Shea B, O'Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. Reference Source\n\nDerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3): 177–88. PubMed Abstract | Publisher Full Text\n\nHiggins JP, Thomas J, Chandler J, et al.: Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane. 2019.\n\nEgger M, Davey Smith G, Schneider M, et al.: Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarbord RM, Egger M, Sterne JAC: A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006; 25(20): 3443–57. PubMed Abstract | Publisher Full Text\n\nPijls B, Jolani S, Atherley A, et al.: Replication Data for: Temporal trends of sex differences for COVID-19 infection, hospitalisation, severe disease, intensive care unit (ICU) admission and death: Aa meta-analysis of 229 studies covering over 10M patients. Harvard Dataverse, V1, UNF:6:tx5Xu/49j5WlDesJc0EUFg== [fileUNF]. 2021. http://www.doi.org/10.7910/DVN/DPP67G\n\nCho SI, Kim YE, Jo SJ: Association of COVID-19 with skin diseases and relevant biologics: a cross-sectional study using nationwide claim data in South Korea. Br J Dermatol. 2021; 184(2): 296–303. PubMed Abstract | Publisher Full Text\n\nJi W, Huh K, Kang M, et al.: Effect of Underlying Comorbidities on the Infection and Severity of COVID-19 in Korea: a Nationwide Case-Control Study. J Korean Med Sci. 2020; 35(25): e237. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee J, Kim M: Estimation of the number of working population at high-risk of COVID-19 infection in Korea. Epidemiol Health. 2020; 42: e2020051. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlsan M, Stantcheva S, Yang D, et al.: Disparities in Coronavirus 2019 Reported Incidence, Knowledge, and Behavior Among US Adults. JAMA Netw Open. 2020; 3(6): e2012403. PubMed Abstract | Publisher Full Text | Free 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 U S A. 2020; 117(44): 27285–91. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoward MC: Gender, face mask perceptions, and face mask wearing: Are men being dangerous during the COVID-19 pandemic? Pers Individ Dif. 2021; 170: 110417. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFalagas ME, Mourtzoukou EG, Vardakas KZ: Sex differences in the incidence and severity of respiratory tract infections. Respir Med. 2007; 101(9): 1845–63. PubMed Abstract | Publisher Full Text\n\nLeung GM, Hedley AJ, Ho LM, et al.: The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med. 2004; 141(9): 662–73. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "125485",
"date": "23 Mar 2022",
"name": "Kevin Wing",
"expertise": [
"Reviewer Expertise Epidemiologist with experience of performing analysis of COVID outcomes in very large datasets and of performing systematic reviews."
],
"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 large and comprehensive systematic review and meta-analysis, the authors looked at the association between sex and COVID-19 health outcomes, screening over 10 000 studies in six different languages from searches of PubMed and EMBASE (between December 2019 and September 2020). Pooled relative risks for 229 selected studies were determined using a random-effects meta-analysis, with a number of factors investigated as potential sources of heterogeneity (including geographical region and time from start of pandemic). Men were shown to have a higher risk for all outcomes overall, with a lower risk for infection and severity of disease and higher risk for death earlier in the pandemic.\nI thought this was an impressive and valuable piece of research, with only a number of minor suggestions for edits, as follows:\nAbstract - it would be helpful to include the start date of the search\n\nIn the first paragraph of the Introduction, please provide a date that supports the phrase \"early phase of the pandemic\" (e.g \"(prior to May 2020)\")\n\nIn Table 1, there are columns of \"case\" and \"control\", which suggests case control studies, although from the underlying data it looks like there were very few of these. I would recommend removing the \"control\" column completely and renaming the \"Case\" column \"Outcome (case)\"\n\nMethods - Study selection section: please rephrase \"Studies were excluded when there was no data on controls\" to read \"Studies were excluded if they only included people with the outcome (cases)\".\n\nMethods - data synthesis and analysis: I was surprised to see that study design (e.g. cohort vs case control vs cross sectional) wasn't included as a subgroup - if numbers of non-cohort studies are a problem then this could be cohort vs other designs (see also comment re: South Korean studies in interpretation).\n\nResults - Study selection section, please rephrase to \"49 only included cases\"\n\nResults - Study characteristics, please add a sentence describing the study designs (e.g. \"X studies were cohort designs, with Y cross-sectional and Z case control\").\n\nResults - In Table 2, the \"Number of patients\" column is blank.\n\nAppendix Forest Plots - the format of the plots for Infection, Hospitalization, and ICU admission (vertical forest plots with countries shown) is much more informative than the plots for Severe Disease and Death - could these two be updated to match the others?\n\nIn the results and appendices \"sensitivity analysis\" are referred to but this term is not used in the methods. I think what is being referred to here is the results of \"subgroup (and meta-regression) analysis\" - it would help if this terminology was used instead of \"sensitivity analysis\" throughout (or \"subgroup (and meta-regression) analysis\" when it first appears, defining that this will be referred to as \"subgroup analyses\" subsequently).\n\nIn the Summary of Evidence section, I did not understand the text after the comma in the sentence \"Additionally, the relative risk of ICU admission increased for men compared to women when the duration of the study increased, suggesting that focus on ICU admission should have sufficient follow-up.\"\n\nIn Interpretation, re: the South Korean studies:\na) could you also comment on whether the two South Korean studies were performed at an early stage of the pandemic i.e. is the early-pandemic effect that you have found also contributing here?\nb) I notice that neither of the South Korean studies are cohort studies (one is cross sectional, the other case control) but non-cohort studies were not investigated as a subgroup.\n\nImplication for clinicians, policymakers, and researchers: I wasn't sure about the statement \"All relative risks that have been presented in this meta-analysis are univariable associations between sex and COVID-19 outcomes\" as it is not specified anywhere in the methods that only unadjusted effects were being pooled. Could this be clarified?\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": "129830",
"date": "22 Apr 2022",
"name": "Helder I. Nakaya",
"expertise": [
"Reviewer Expertise Data science",
"bioinformatics",
"immunology",
"systems 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\nPijls et al provided a comprehensive meta-analysis that shows the temporal trends of sex differences for different COVID-19 outcomes. The study selection, the meta-analysis itself (following PRISMA), statistical analysis, and conclusions are appropriate. However, the main conclusion (men are more infected and have an increased risk of severe COVID-19 than women) was shown by several people. It is not clear whether the authors had access to demographic and clinical anonymized information of all 10M+ patients. If so, this data should be provided.\nAs studies themselves have different characteristics regarding the recruited patients (comorbidities, age group, etc), I wish the authors had focused on trying to explain which conditions these relative risks are much higher or much lower in men. Also, (as stated in the \"limitations and strengths\") this manuscript only contains data from the first wave of COVID-19 mostly. It would be interesting to see these risks over the different waves and variants.\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/11-5
|
https://f1000research.com/articles/10-200/v1
|
10 Mar 21
|
{
"type": "Systematic Review",
"title": "Current status of insecticide resistance in malaria vectors in the Asian countries: a systematic review",
"authors": [
"Dewi Susanna",
"Dian Pratiwi",
"Dian Pratiwi"
],
"abstract": "Background: The application of insecticides for malaria vector control has remained a global problem, due to the current trend of increased resistance against these chemicals. This study aims to determine the insecticide-resistant status in Asia and how to implement the necessary interventions. Moreover, the implications of resistance in malaria vector control in this region were studied. Methods: This systematic review was conducted using a predefined protocol based on PRISMA-retrieved articles from four science databases, namely ProQuest, Science Direct, EBSCO, and PubMed in the last ten years (2009 to 2019). The searching process utilized four main combinations of the following keywords: malaria, vector control, insecticide, and Asia. In ProQuest, malaria control, as well as an insecticide, were used as keywords. The following criteria were included in the filter, namely full text, the source of each article, scholarly journal, Asia, and publication date as in the last ten years. Results: There were 1408 articles retrieved during the initial search (ProQuest=722, Science Direct=267, EBSCO=50, PubMed=285, and Scopus=84). During the screening, 27 articles were excluded because of duplication, 1361 based on title and abstract incompatibility with the inclusion criteria, and 20 due to content differences. In the final screening process, 15 articles were chosen to be analyzed. From the 15 articles, it is known that there was dichlorodiphenyltrichloroethane (DDT) and pyrethroids resistance in several anopheles species with a mortality rate of less than 80%. Conclusions: The report on the pyrethroid resistance was complicated, since this insecticide was considered effective in malaria vector control. Therefore, several strategies were required, including the management plans in selecting insecticides, using a rotation system during interventions in the field, regular monitoring, and integrating vector control based on physics, chemistry, and biology. All of these need to be supported by cross-sector policies and cooperation in achieving the 2030 malaria-free target.",
"keywords": [
"Anopheles",
"Malaria Elimination",
"Vector Control Program",
"Insecticide Resistance",
"Asian Countries"
],
"content": "Introduction\n\nMalaria is one of the most common vector-borne diseases widespread in the tropics and subtropics1. According to the World Malaria Report (2019), an estimated 219 million cases were recorded in 2017, compared to the 217 million in the previous year2. The global estimate of deaths caused by malaria reached 435,000 cases, which was the same number in 20163. The use of insecticides is the basis for the effective control of vectors, and this process has played an essential role in the management and elimination of malaria4.\n\nThe prevention of malaria mainly depends on one class of insecticides, namely pyrethroids; however, the increase in resistance to it reduces this treatment's efficacy5. The progressive reduction of malaria's burden through substantial improvements of insecticide-based vector control in recent years is reversible by the emergence of widespread resistance to this chemical6. Insecticide resistance is widespread and is now reported in almost two-thirds of the countries with ongoing malaria transmission. This resistance affects all major vector species and groups of insecticides7.\n\nVector control is an essential aspect of a program organized to manage the disease transmitted by this type of organism. The use of insecticides for this process is an effective strategy; however, it is also related to the development of resistance in targeted vectors and is one reason for the failure of disease control in many countries8. Since 2000, malaria cases have halved due to the management and vector control interventions, estimated to have saved 660 million people9. The global commitment to eliminate malaria by 2030 requires immediate efforts that include the establishment of infrastructure for monitoring regular insecticide resistance, the development of combined and effective control products10.\n\nThis review aimed to determine the status of insecticide resistance in Asia and how to implement interventions. It is also expected that this sets an example for other countries in the vector control program and provides guidance for insecticides and malaria risk reduction.\n\n\nMethods\n\nThis study retrieved articles from four science databases, namely ProQuest, Science Direct, EBSCO, and PubMed, from December 2009 to December 2019. A systematic review was conducted using a predefined protocol based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA)11,12. The searching process utilized four main combinations of the following keywords: “malaria”, “vector control”, “insecticide”, and “Asia”. In order to reduce the risk of bias from the articles obtained, the researchers conducted disbursements in all databases using the same keywords and on the same day.\n\nIn ProQuest, “malaria” and “vector control”, as well as “insecticide”, were used as keywords. The full text, the source of an article, scholarly journal, Asia, and date of publication as in the last ten years were included in the filter. The search strategy and filter used in Science Direct were the same as that above except \"Asia\". In EBSCO, a similar keyword was also used. The limiters were the same as the filter in the Proquest, but also included \"abstract available\". In the Pubmed, the terms used were as follows, (\"malaria\"[MeSH Terms] OR \"malaria\"[All Fields]) AND (\"vector\"[MeSH Terms] OR \"vector\"[All Fields]) AND (\"control\"[MeSH Terms] OR \"control\"[All Fields]) AND (\"insecticide\"[MeSH Terms] OR \"insecticide\"[All Fields]) AND (\"loattrfulltext\"[sb] AND \"2009/12/02\"[PDat] : \"2019/12/02\"[Pdat])s.\n\nOriginal articles (academic or research papers) in Asia, written in English and published in the last ten years were included. Study designs such as prospective study, review, cross-sectional, cohort, and case control were included. Articles about biochemical, resistance to dieldrin (RDL) mutation, knowledge and attitudes, and spatial modeling were excluded because that can cause different results. Articles about malaria but including nothing about insecticides were excluded. The implications of insecticide resistance in related countries were investigated. Studies that were not relevant to this study were excluded.\n\nThe articles' eligibility was determined from each title, abstract, and full text by two reviewers (DP and DS). DP and DS also independently screened the articles for inclusion and extracted data on general information. To solve any disagreements and problems during the study, regular meetings were held by the researchers to discuss issues.\n\nThe search strategy and inclusion and exclusion criteria were validated and implemented. The initial database was then created from the electronic search. All citations were first filtered by title and abstract, and duplicates omitted. The full texts of eligible papers were then obtained independently for further filtering. After resolving the differences in data extraction or interpretation through consensual discussions based on the inclusion and exclusion criteria mentioned above, the final papers were selected.\n\nThe data from the chosen eligible studies were the authors, study period, publishing year, the country where it was conducted, settings, location characteristics, bioassay methods, the sample of Anopheles mosquito, and the quartiles in SCImagoJR. SCImagoJR is a publicly available portal that includes the journals and country scientific indicators developed from the information contained in the Scopus database. The findings were arranged according to the objective and result obtained in related implications of malaria vector control resistance. Throughout the entire selection process, the use of insecticides in the bioassay method, the associated mortality rate of the Anopheles mosquito, and its implementation in the specific areas were reported to illustrate the practice's pattern and extent.\n\nAll variables for which we extracted data ware Anopheles species, vector habitat, bioassay method, insecticides, mortality rate, insecticide resistance strategies/intervention. The differences in methods could bias the results; to reduce this bias, we selected articles with a similar method. For articles about insecticide resistance, we only looked at articles using bioassay with the world health organization (WHO) standard13. The WHO bioassay is carried out with paper impregnated from four main classes of insecticides in common use, with different concentrations according to the WHO test procedure14.\n\n\nResults\n\nThe identification process for review is outlined in Figure 115. There were 1,408 articles retrieved during the initial searching (ProQuest=722, Science Direct=267, EBSCO=50, Pubmed=285 and Scopus=84). Through screening, 27 articles were excluded because of duplication, 1,361 based on title and abstract incompatibility and 20 due to inconsistency with the inclusion criteria; 15 were chosen to be analyzed.\n\nThe 15 eligible articles originated from eight Asian countries published from 2012 to 2019 journals are shown in Table 1.\n\nThere were 23 species of Anopheles from these studies (Table 2). In several countries, the main vectors included An. stephensi (Iran), An. superpictus (Afghanistan), An. culicifacies (India), An. minimus and An. maculatus (Lao and Thailand), An. sinensis (China), An. subpictus (Sri Lanka), and An. sacharovi (Turkey). From Table 2, the malaria vector was divided into three habitats, based on distribution, namely in rice fields, forests and on the coast, and flowing rivers. The differences in the main vector of each country depended on environmental/ecological conditions, living habitat, as well as the feeding and resting behavior of each Anopheles.\n\nThe entire female Anopheles collected was morphologically identified for their species or complexes using stereomicroscopes and morphological keys16. The mosquitoes were separated into groups of species, complexes, or bioassay, then kept alive by giving them a sugar solution17.\n\nAnopheles mosquitoes were morphologically identified at the adult stage using the Glick identification key18. The susceptibility tests were carried out following the WHO guidelines for monitoring resistance in malaria vectors. From 15 papers reviewed, the impregnated with insecticides of DDT (4%), malathion (5%), bendiocarb (0.1%), propoxur (0,1%), deltamethrin (0.05%) and l-cyhalothrin (0.05%), cyfluthrin 0.15%, permethrin 0.75%, and etofenprox 0.5% was prepared by adopting the WHO standard method14 (Table 3).\n\nWHO=world health organization. DDT=dichlorodiphenyltrichloroethane. NA= not available.\n\nThe insecticide bioassay was then carried out using a recommended standard WHO kit13. The mortality rate was recorded 24 hours after exposure, while the average death was calculated for each insecticide and according to the WHO criteria19. Bioassay results were summarized in three resistance classes according to the WHO criteria12: (1) susceptible when death was 98% or higher, (2) resistance-possibility was tolerable when mortality was between 97% and 80%, and (3) resistant when death case was lower than 80%18.\n\nThe highest mortality rate (MR) ≥ 98% of etofenprox application was on An. stephensi in Iran. While permethrin application was on An. superpictus (Afghanistan), An. nivipes (Thailand), An. philipinensis (Lao and Thailand), and An. tesselatus (Lao). Then, bendiocarb and malathion were on An. culicifacies (India and Afghanistan). Also, deltamethrin was on An. anularis (India), An. barbirostris, An. dirus, An. karwari (Thailand), An. vagus (Thailand and China), An. maculatus (Lao and Thailand), and An. umbrosus (Lao). An minimus (Thailand Myanmar Border), Meanwhile, permethrin and deltamethrin were on An. aconitus, and An. kochi (Lao). Lastly, lambda cyalothrin and deltamethrin were on An. sundaicus (Sri Lanka), with MR ≤ 97% indicating resistance-possibility based on the WHO classification.\n\nTable 4 shows the level of anopheles resistance to organochlorine (dichlorodiphenyltrichloroethane; DDT), organophosphate (malathion), carbamate (bendiocarb and propoxur), and pyrethroid (permethrin, deltamethrin, lambda cyalothrin, cyfluthrin, and etofenprox). Almost all the species of this mosquito studied were possibly resistant to DDT. Furthermore, this similar issue has been reported in An. stepensi, An. superpictus, An. culicifacies, An. vagus, An. sinensi, An. subpictus, and An. sachrovi to malathion. Also, it was found in An. superpictus and An. sachrovi to propoxur as well as in An. umbrosus to permethrin. The same was in An. sinensis, An. superpictus, An. sundaicus, An. minimus, An. maculatus and An. jamessi to deltamethrin. Resistance was also reported in An. stephensi, An. culcifacies, An. vagus, and An. barbirostris to permethrin and deltamethrin, and in An. stephensi to etofenprox. However, direct resistance was found in An. hyrcanus to Permethrin and deltamethrin, as well as in An. culicifacies to lambda cyalothrin. Also, this was found in An. stephensi, An. sinensis and An. culicifacies to cyfluthrin.\n\n*Main vector\n\nDDT=dichlorodiphenyltrichloroethane. NA=not available, S=Susceptible (90-97% mortality suggest), P=Possible Resistance, R=Resistance= < 90%.\n\nTable 5 shows that insecticide resistance interventions in several Asian countries are through vector prevention by environmental, biological, and chemical management. Implementation is through insecticide rotation monitoring, mapping, and surveillance. Malaria eradication started from effective prevention, technical capability approaches, government and community support, funding sources, accurate data, and adequate implementation.\n\n\nDiscussion\n\nEcologically, the sites used were mountainous, harbor/seaport, mixed thicket/ lush and dense forests, humid climate, rivers, rice fields, and ponds that provide a suitable environment for vector mosquito breeding. Anopheles mosquitos' seasonal activity differs in various regions due to environmental conditions20. Also, those collected were identified for species based on their morphological characteristics19,21.\n\nThe application of chemical insecticides is one of the most critical interventions for malaria control, which included organochlorines (DDT, dieldrin, and BHC), organophosphates (pyrimytophos-methyl and malathion), carbamates (propoxur), and pyrethroids (lambda-cyhalothrin and deltamethrin). And were used in various forms of application, such as indoor residual spraying (IRS) and insecticide-treated mosquito nets (ITNS) for controlling adult mosquitos. In contrast, organophosphates for larviciding were used in malaria-prone areas22. Currently, the pyrethroids were used in various Asia countries for ITNs and long-lasting insecticidal nets (LLINs). They were also considered the most effective because of their advantages, namely low mammalian toxicity, rapid knockdown activity, and high efficacy against a wide range of insect pests, especially mosquitos22.\n\nResistance to various insecticide classes was a common problem in different malaria vector species. This situation has been reported and is shown in Table 5, including widespread resistance to DDT and pyrethroids23. The multiple resistance of reported malaria vector Included An. stephensi, An. superpictus, An. culinary, An.annularis, An. minimus, An. hyrcanus, An. barbirostris, An. vagus, An. maculatus, An. jamessi, An nivipes, An. philippinensis, An. umbrosus, and An. sinensis in Asia. Most of the new reports were towards pyrethroid compounds, the only insecticides used for LLINs22. This became a challenge for malaria control and elimination, therefore, using the same insecticide for multiple successive IRS cycles is not recommended; preferably a rotation system with various types of these groups, including carbamates, should be used33. The rotation should start with an insecticide that has the lowest resistance frequency. In high-coverage areas with LLINs, pyrethroids were good choices for IRS because this added to the selection pressure.\n\nFurthermore, using an impregnated net synergistically with synthetic pyrethroid was a better choice for malaria vectors resistant to this class of chemical. The mixed nets, such as the aforementioned, have applications against resistible mosquitoes, mainly based on oxidative metabolism34. Since monitoring of the resistance was a critical element for implementing insecticide-based vector control interventions, there was a need for periodic surveillance at least once a year or preferably every six months13.\n\nThe mortality test category was in the range between 98–100%, 80–97%, and <80%, and was categorized as susceptible, possibly resistant, and resistant population, respectively23. All vectors had resistance to DDT with a value below 80%; however, the use of insecticide began to decline gradually over the last few decades and was removed entirely from malaria control in 2000. This decline was due to the perceived adverse effects on the environment and decreased public acceptance for spraying indoor residues35.\n\nPyrethroids were the most commonly used insecticides for ITN and IRS, which target indoor transmission and mosquitos that bite in the room29. The mortality rate was <80% for the pyrethroid group in An. vagus, An. culinary, An. stephensi, An. hyrcanus, An. barbirostris, An. superpictus, An. sacharovi, and An. subpictus. This proved that pyrethroid was less effective. Meanwhile, insecticide resistance was present in malaria vectors in Asia, and the genes spread rapidly throughout the world36.\n\nThe use of insecticides to reduce vector populations has become the main strategy for malaria control. Presently, 12 of these interventions belonging to four chemical classes are recommended by the WHO Pesticide Evaluation Scheme (WHOPES) for IRS37. Current strategies for controlling malaria vectors mainly include IRS with synthetic DDT/pyrethroids and durable LLINs14. WHO recommends that these insecticides' susceptibility status needs to be monitored annually13. However, the last two decades have seen the use of insecticides everywhere, especially pyrethroids, causing widespread resistance and compromising the effectiveness of vector control38. Besides, when this situation is detected, the intensity, biochemical and molecular mechanisms should also be investigated. The accurate information about the underlying resistance mechanism and its intensity or frequency in the malaria vector turn to update the vector control program and ensure the timely management of insecticide resistance23. Therefore, biochemical and molecular tests are recommended to understand the mechanism of pyrethroid resistance, and there have been several reports about this situation in the malaria vectors. However, several control strategies are used to fight resistance, such as rotation, mixture, using biological control, and integrated vector management27.\n\nThis study had limitations, such as the dissimilar variables investigated, which produced an incomplete analysis. There were only 15 articles from eight countries that correlated with the inclusion criteria from the selected ten years of studies. The data on each country's mortality rate presented only the smallest value, therefore, making it difficult to explore the whole data that need to make the discussion complete. In some countries, the bioassay test did not use carbamate, even though it was effective for controlling certain types of Anopheles.\n\n\nConclusion\n\nThe reports of pyrethroid resistance were quite focused on because it is considered effective in the malaria vector control. Several strategies are needed, including management plans in selecting insecticides, using a rotation system during the field interventions, regular monitoring, and integrating vector control based on physics, chemistry, and biology. All these need to be supported by cross-sector policies and cooperation to achieve the 2030 malaria-free target.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: PRISMA 2009 checklist for an article entitled Current status of insecticide resistance in malaria vectors in the Asian countries: systematic review. https://doi.org/10.6084/m9.figshare.1358607815.\n\nThis project contains the following extended data:\n\n- PRISMA flow diagram of systematic review inclusion and exclusion process\n\nFigshare: PRISMA checklist for ‘Current status of insecticide resistance in malaria vectors in the Asian countries: systematic review’. https://doi.org/10.6084/m9.figshare.1358251712.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Authors’ contributions\n\nDS contributed in designing and conducting the study, and also writing the draft of the manuscript, while DP searched and extracted the used data from the databases. The authors analyzed, edited, read, and approved the final manuscript in the English language. DS: Funding Acquisition of the financial support for the project leading to this publication.\n\n\nAcknowledgments\n\nThe authors are grateful to the Directorate of Research and Community Engagement for giving the Indexed International Publication for Project grant and financial support. Authors also would like to thank MS. Rusyda Ihwani Tantia NOVA, SKM, M.Kes for her comments for improving this work.\n\n\nReferences\n\nWorld Health Organization: Anopheline Species Complexes in South and South-East Asia. no. 57. 2007. Reference Source\n\nWorld Health Organization: World malaria report 2018. Switzerland: World Health Organization, 2018. Reference Source\n\nWorld Health Organization: Malaria Surveillance, Monitoring & Evaluation: a Reference Manual. Global Malaria Programme -WHO, 2018. Reference Source\n\nEnayati A, Hemingway J: Malaria management: Past, present, and future. Annu Rev Entomol. 2010; 55: 569–591. PubMed Abstract | Publisher Full Text\n\nHemingway J, Ranson H, Magill A, et al.: Averting a malaria disaster: will insecticide resistance derail malaria control? Lancet. 2016; 287(10029): 1785–1788. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKleinschmidt I, Mnzava AP, Kafy HT, et al.: Design of a study to determine the impact of insecticide resistance on malaria vector control: A multi-country investigation. Malar J. 2015; 14: 282. 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Indian J Med Res. 2015; 142 Suppl(Suppl 1): S59–63. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChaumeau V, Zadrozny J, Cerqueira D, et al.: Insecticide resistance in malaria vectors along the Thailand-Myanmar border. Parasit Vectors. 2017; 10(1): 165. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDhiman S, Rabha B, Goswami D, et al.: Insecticide resistance and human blood meal preference of Anopheles annularis in Asom-Meghalaya border area, Northeast India. J Vector Borne Dis. 2014; 51(2): 133–136. PubMed Abstract\n\nGorouhi MA, Oshaghi MA, Vatandoost H, et al.: Biochemical Basis of Cyfluthrin and DDT Resistance in Anopheles stephensi (Diptera: Culicidae) in malarious area of Iran. J Arthropod Borne Dis. 2018; 12(3): 310–320. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Global plan for insecticide resistance management in malaria vectors (GPIRM). France: WHO GLOBAL MALARIA PROGRAMME, 2012. Reference Source\n\nAhmad M, Buhler C, Pignatelli P, et al.: Status of insecticide resistance in high-risk malaria provinces in Afghanistan. Malar J. 2016; 15: 98. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChand G, Behera P, Bang A, et al.: Status of insecticide resistance in An. culicifacies in Gadchiroli (Maharashtra) India. Pathog Glob Health. 2017; 111(7): 362–366. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChareonviriyaphap T, Bangs MJ, Suwonkerd W, et al.: Review of insecticide resistance and behavioral avoidance of vectors of human diseases in Thailand. Parasit Vectors. 2013; 6: 280. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVatandoost H, Hanafi-Bojd AA: Indication of pyrethroid resistance in the main malaria vector, Anopheles stephensi from Iran. Asian Pac J Trop Med. 2012; 5(9): 722–726. PubMed Abstract | Publisher Full Text\n\nMarcombe S, Bobichon J, Somphong B, et al.: Insecticide resistance status of malaria vectors in Lao PDR. PLoS One. 2017; 12(4): e0175984. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQin Q, Li Y, Zhong D, et al.: Insecticide resistance of Anopheles sinensis and An. vagus in Hainan Island, a malaria-endemic area of China. Parasit Vectors. 2014; 7: 92. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDai Y, Huang X, Cheng P, et al.: Development of insecticide resistance in malaria vector Anopheles sinensis populations from Shandong province in China. Malar J. 2015; 14: 62. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSurendran SN, Jude PJ, Weerarathne TC, et al.: Variations in susceptibility to common insecticides and resistance mechanisms among morphologically identified sibling species of the malaria vector Anopheles subpictus in Sri Lanka. Parasit Vectors. 2012; 5: 34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYavaşoglu Sİ, Yaylagül EÖ, Akıner MM, et al.: Current insecticide resistance status in Anopheles sacharovi and Anopheles superpictus populations in former malaria endemic areas of Turkey. Acta Trop. 2019; 193: 148–157. PubMed Abstract | Publisher Full Text\n\nRaghavendra K, Verma V, Srivastava HC, et al.: Persistence of DDT, malathion & deltamethrin resistance in anopheles culicifacies after their sequential withdrawal from indoor residual spraying in Surat district, India. Indian J Med Res. 2010; 132: 260–264. PubMed Abstract\n\nPennetier C, Bouraima A, Chandre F, et al.: Efficacy of Olyset® Plus, a New Long-Lasting Insecticidal Net Incorporating Permethrin and Piperonil-Butoxide against Multi-Resistant Malaria Vectors. PLoS One. 2013; 8(10): e75134. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChareonviriyaphap T, Bangs MJ, Suwonkerd W, et al.: Review of insecticide resistance and behavioral avoidance of vectors of human diseases in Thailand. Parasit Vectors. 2013; 6: 280. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRanson H, N’Guessan R, Lines J, et al.: Pyrethroid resistance in African anopheline mosquitoes: What are the implications for malaria control? Trends Parasitol. 2011; 27(2): 91–98. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: WHO recommended insecticides for indoor residual spraying against malaria vectors. no. October, 2013; 2013. Reference Source\n\nThomsen EK, Hemingway C, South A, et al.: ResistanceSim: Development and acceptability study of a serious game to improve understanding of insecticide resistance management in vector control programmes. Malar J. 2018; 17(1): 422. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "87116",
"date": "30 Jun 2021",
"name": "Josiane Etang",
"expertise": [
"Reviewer Expertise Medical entomology"
],
"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 emergence and spread of Anopheles resistance to insecticides is a growing issue, that jeopardizes the effectiveness of currently available core malaria vector control tools, i.e. Long Lasting Insecticidal nets (LLINs) and Indoor Residual Spraying (IRS).\nBased on data extracted from 15 original articles selected from four science databases, the authors of this paper came out with a baseline review on malaria vector resistance status in Asia. This resistance concerns 23 anopheline species collected in 8 countries between 2012 and 2019, to 10 insecticides belonging to the four chemical classes mostly used for vector control. Additional information on the ecology and habitat of malaria vectors is also provided. Yet, the authors suggested some resistance management strategies, including the selection of insecticides to be used for vector control, the rotation of the interventions, and integrating vector control methods.\nHowever, as a limitation, the low number and the content of the articles that were eligible for this study (15 papers) made it difficult to thoroughly investigate the geographic and structural distribution of insecticide resistance in target countries, as well as the underlying resistance mechanisms. It appears that the drawn conclusions are partly supported by the results of the review. Furthermore, several issues should be addressed to improve the manuscript:\n1. Abstract\nLine one: \"remained\" may be replaced by \"led to\"; and \"due to\" replaced by \"which is\".\n\nLine two: The study aims to \"review\" the insecticide resistance status which was previously determined.\n\nConclusion: I would suggest replacing \"complicated\" with \"challenging\".\n2. Introduction\nParagraph 1: please update the situation of malaria, according to the world malaria report 2020.\n\nParagraph 2: please add \"partly\" before \"reversible\", because there are many other factors that may hinder the reduction of malaria burden apart from insecticide resistance.\n\nParagraph 3: It is not clear which type of organism the authors are talking about in the first sentence of this paragraph. At the end of the paragraph, please change the position of \"regular\" and place it before \"monitoring\"; i.e. \"regular monitoring\".\n3. Methods\nIn the last paragraph, it is said that only papers dealing with the WHO bioassay protocol were considered. Currently, the CDC bottle assay is also used for insecticide resistance testing and monitoring. Adding a separate analysis of resistance data from the CDC bottle assay, if any, could probably increase the amount of resistance data.\n\n4. Results\nParagraph 1: A map showing the countries where insecticide resistance has been reported and the recorded resistance status for each insecticide used is missing.\n\nParagraph 2: Please delete \"In several countries\" since each species is associated with only one or two countries and not all the countries. Also, it is not clear how a malaria vector can be divided into three habitats; and also which malaria vector the authors are talking about?\n\nParagraph 3: Please consider revising the first sentence of this paragraph, e.g. All the female Anopheles collected were morphologically identified for their species/complexes...\". The last sentence about mosquito processing is also confusing; the authors may consider revising it.\n\nParagraph 4: Please include \"papers\" before \"impregnated\" and replace \"was\" with \"were\".\n\nParagraph 5: Please delete \"summarized in three resistance classes\", this is confusing. The authors may just state that \"bioassay results were analyzed according to WHO criteria. Also, the reference N°12 is not specific to WHO bioassay protocol, same as reference n°18; please consider revising the numbering of the references. The reference n°13 is appropriate for this paragraph.\n\nRegarding the interpretation of the results, the authors should check, which of the WHO protocols they used. In the running WHO protocol which was deriving the revision made in 2018, the criteria for interpretation of bioassay results are different from the criteria presented in this paragraph. In the revised protocol, the resistance threshold is 90%, not 80%.\n\nParagraph 6: A mortality rate <97% is wide and also includes confirmed resistance, please specify the lowest mortality rates indicating possible resistance.\n\nParagraph 8: The first sentence may be as follows: \"Table 5 shows that the insecticide resistance management strategies in several Asian countries are through vector control by environmental, biological, and chemical interventions. The implementation of chemical interventions is through insecticide rotation, monitoring their bioefficacy, mapping, and surveillance of malaria vectors. Malaria eradication relies on...\"\n5: Discussion\nHere are suggestions for subtitles: Types of insecticides, Insecticide resistance frequencies, Mortality rates of Anopheles populations, Interventions.\n\nParagraph 2: Types of insecticides - In the second sentence of the paragraph, please replace \"And\" with \"These chemicals\". Also, replace \"Currently\" with \" Actually\".\n\nParagraph 3: Insecticide resistance frequencies - No need to refer to tables in the discussion.\n\nThe authors may combine the first and the second sentences of this paragraph; e.g. \" Resistance to various insecticides, especially to DDT and pyrethroids, was common...vector species. Multiple insecticide resistance was reported in 14 malaria vector species in Asia; these include A. stephensi...A. sinensis.\" For the last sentence of this paragraph and the first sentence of the next paragraph, the authors should refer to WHO guidelines for using both LLINs and IRS in specific conditions. Please consider replacing \"resistible mosquitoes\" with \"resistant mosquitoes\".\n\nParagraph 6: Mortality rates of the Anopheles - What is the mortality test? Is it the susceptibility test? The author should consider revising the first sentence of this paragraph. It is not clear how a test can be in a range of 98-100%, 80-97%... etc.\n\nParagraph 8: In the second sentence of this paragraph, the authors may replace \"interventions belonging to...\" with \"insecticides belonging to...\" and delete \"durable\" from the next sentence.\nThe following sentences should also be revised as follows:\n\" The accurate information about...tuns...of insecticide resistance\". \"Therefore, biochemical...understand the mechanisms...in malaria vectors\". \"However, several control strategies...used to overcome resistance...vector management\".\n6. Conclusion The following sentences should also be revised as follows:\nThe reports of pyrethroid resistance were quite challenging, because...\" \"integrating vector control strategies based on physical, chemical and biological methods\".\n7. Tables\nTable 1. The title of this table may be \"Article description\" rather than \"charactéristics\".\n\nColumn 3 may be title \"year of publication\" rather than \"publish\".\n\nTable 2: The title of this table may be \"Mosquito species and their types of habitat\" rather than \"sample and location characteristics\".\n\nTable 4. The title of this table may be \"Anopheles mortality rates in insecticide resistance bioassays\" rather than \"Mortality rate of insecticide resistance bioassay in Anopheles\".\n\nTable 5: The title of this table may be as follows \" Insecticide resistance management strategies\".\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
},
{
"id": "93580",
"date": "01 Oct 2021",
"name": "Charles M. Mbogo",
"expertise": [
"Reviewer Expertise Medical Entomology"
],
"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 reporting on insecticide resistance data compiled through systematic review from Asian countries. The purpose of this systematic review was to understand the current status of insecticide resistance among malaria vectors and the implementation of the interventions.\nIntroduction/Background:\nThe background information is sound, and the research question is easily identifiable. However, a few minor comments:\nParagraph 2 --- “The prevention of malaria mainly depends on one class of insecticides, namely pyrethroids; however, the increase in resistance to it reduces this treatment’s efficacy”. This sentence is not clear because malaria control may be done using the 4 available classes of insecticides and not the pyrethroids unless one is talking about LLINs.\n\nParagraph 3 –states that “Vector control is an essential aspect of a program organized to manage the disease transmitted by this type of organism”. Be specific and state what kind of organism is this.\n\nMethods:\n\nThe methodologies applied are appropriate and adequately described. The searching process used was also appropriate. However, the authors indicated that they selected the 15 papers based on several criteria of which one included WHO bioassay protocol on the four major insecticide classes and did not consider any other bioassay protocols such as CDC bottle assay.\nCurrently, insecticide resistance is measured using WHO bioassay protocol and CDC bottle assay. It is important to check if any of the selected publications had any analysis of resistance including CDC bottle assay. If this is correct, then consider it as it could increase the amount of resistance data.\nResults:\nThe results are coherently described with tables and figures. However, Tables 2, 3, 4, & 5 should have clear and legible descriptions.\nParagraph 2 …” From Table 2, the malaria vector was divided into three habitats …”. This sentence needs to be rephrased to make it clear. How can mosquito vectors be divided into three habitats or what do you mean? The sentence that follows this in the same paragraph should also be rephrased for clarity.\n\nParagraph 3 …. “The entire female Anopheles collected was morphologically identified for their species or complexes using stereomicroscopes and morphological keys” The whole of this paragraph and the next one should be combined and written clearly to convey the necessary message.\n\n“From 15 papers reviewed, the impregnated with insecticides of DDT (4%)…” Insert the word “papers” before impregnated.\n\nParagraph 8 … “Table 5 shows…” Consider revising this paragraph to make it clear.\n\nDiscussion and Conclusion\nThe discussion highlights the different aspects of the findings on the status of insecticide resistance in different Asian countries. These are partly discussed in relation to the current literature and the status of insecticide resistance in the region. However, more discussions are required on the outcomes on the types, levels, and intensity of insecticide resistance and how multiple insecticide resistance was reported in the diversity of malaria vectors present in the region. Below are a few minor issues that need to be addressed:\nPage 12, Paragraph 1: ”This became a challenge for malaria control and elimination, therefore, using the same insecticide for multiple successive IRS cycles is not recommended”. Revise this sentence and the entire paragraph to make it clear.\n\nPage 12, paragraph 2: “…applications against resistible mosquitoes”. Which are these mosquitoes?\n\nPage 12, paragraph 4: “This proved that pyrethroid was less effective. Meanwhile, insecticide resistance was present in malaria vectors in Asia, and the genes spread rapidly throughout the world”. This statement is misleading ..what evidence do you have that resistance genes were spreading quickly throughout the world?\n\nPage 12, paragraph 5: It is important to state some of the 12 interventions mentioned here and their challenges and opportunities they have.\n\nConclusion: The conclusion is not fully drawn from the analysis of this systematic review?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-200
|
https://f1000research.com/articles/10-1126/v1
|
08 Nov 21
|
{
"type": "Opinion Article",
"title": "Grant writing and grant peer review as questionable research practices",
"authors": [
"Stijn Conix",
"Andreas De Block",
"Krist Vaesen",
"Andreas De Block",
"Krist Vaesen"
],
"abstract": "A large part of governmental research funding is currently distributed through the peer review of project proposals. In this paper, we argue that such funding systems incentivize and even force researchers to violate five moral values, each of which is central to commonly used scientific codes of conduct. Our argument complements existing epistemic arguments against peer-review project funding systems and, accordingly, strengthens the mounting calls for reform of these systems.",
"keywords": [
"peer review",
"grant review",
"project funding",
"research ethics",
"ethics of funding",
"science funding"
],
"content": "1. Introduction\n\nIn industrialized societies, a large fraction of the governmental budgets for research is allocated through competitive peer review of project proposals. This popular mode of funding allocation has been criticized for not delivering the scientific goods it was intended to deliver. Evidence has shown that grant peer review is costly, that the ranking it produces lacks validity, and that it does not promote novel views (Guthrie, Ghiga, and Wooding 2018; Herbert et al. 2013; Link, Swann, and Bozeman 2008 and other references below). But whereas the epistemic defects of peer-review project funding (PRPF) have been extensively studied, its ethical shortcomings have received little scholarly attention. It is these ethical shortcomings that the current paper is concerned with. More specifically, we will argue that PRPF systems prompt behaviour that violates moral values and norms that, according to prominent scientific codes of conduct, scientists, funding agencies and other stakeholders of PRPF are expected to conform to.\n\nAs we will see, PRPF systems exert a whole range of different pressures on applicants, reviewers and funders to behave unethically. Importantly, these pressures vary in strength. Sometimes, the pressures are best thought of as (mere) incentives. Those incentives make it more likely that individual researchers will act unethically, primarily because such morally questionable behaviour will increase their chances of success in grant acquisition. Yet, such incentives do not really require researchers to engage in unethical practices. On the other hand, there are also what we will call ‘forces’. Because of these forces, researchers who want to apply for research funding or who agree to serve as a grant-decision maker are required to behave in a way that most researchers deem ethically questionable.\n\nThe conclusion of this paper is that the academic community should reconsider its widespread use of PRPF systems, not just because of these systems’ (alleged) inefficiency and epistemic shortcomings, but also because they almost inevitably promote ethically questionable behaviour.\n\nIn the next section, we briefly discuss the background, prominence and epistemic shortcomings of PRPF. The third section analyses prominent scientific codes of conduct (CoC) to identify the ethical values that are supposed to guide the behaviour of researchers. The fourth section then argues that PRPF systems come with a whole range of incentives and forces that prompt violations of these values. Finally, the fifth section discusses what is needed to make the allocation of research funding more ethical.\n\n\n2. PRPF: background, prominence and epistemic shortcomings\n\nSince the 1970s, governments have distributed an increasing fraction of their resources for research on the basis of competition, following a model that the American National Science Foundation (NSF) put in place in the 1950s (England 1982). These governments urged funding agencies to organize competitions among researchers, such that project proposals are assessed by academic peers, in a way analogous to the peer review of scientific articles.\n\nAt present, science funding agencies in industrialized societies allocate much of their funding through PRPF.1 In the US, for example, the National Institutes of Health (NIH) annually invests over $30 billion in basic and applied biomedical research. All of that money is allocated through PRPF. The same holds true for the budget that the NSF spends on basic research (about $8.8 billion per year).2 The European Union, finally, allocated about €60 billion through PRPF between 2014 and 2020 with its Horizon 2020 programme (Schiermeier 2020).\n\nThe currently widespread reliance on PRPF has a series of consequences for researchers. Trivially, peer review of grant proposals influences what kind of research will be done, and who gets to do it. Successful applications also come with prestige, both within and outside the research community (Coate and Howson 2016). Relatedly, research careers can be made or broken by grant applications. Many research institutions now make tenure, promotions and salary raises dependent on a researcher’s success in prestigious calls (Dunn, Iglewicz, and Zisook 2020; Joiner and Wormsley 2005). For example, several European universities give a substantial salary supplement to successful ERC-applicants for the duration of their project. In Germany, there is a bonus system for professors that regularly includes targets for grant acquisitions.3\n\nGiven its crucial role in today’s science, one would expect that PRPF reliably and efficiently selects the best scientific projects. Yet, the literature on research funding has raised serious doubts about this. Several studies indicate that peer review is not a very reliable or valid method for evaluating research proposals. Regarding reliability, Kaplan et al. (2008), for instance, argue that for the mandated level of precision in reviewers’ scores, the NIH needs as many as 40,000 reviewers per project instead of the 4 reviewers it now aims for. Moreover, biases such as cronyism are pervasive in grant funding (van den Besselaar 2012; Guthrie, Ghiga, and Wooding 2018).\n\nSince low reliability implies low validity, it should not come as a surprise that reviewers often fail to predict the scientific success of the proposals they evaluate. For instance, there is no or only a weak correlation between the review score of a project and its eventual bibliometric impact (Doyle et al. 2015; Fang, Bowen, and Casadevall 2016; van den Besselaar and Sandström 2015). Plenty of anecdotal evidence suggests that review panels do a poor job at predicting success: Nobel Prize laureates have repeatedly complained about the difficulties they have experienced in getting their award-winning work past grant review committees (Bendiscioli 2019; Johnson et al. 2010; Kim 2006; Marshall 2005; Taubes 1986).\n\nOther epistemic problems relate to the types of knowledge that are generated by PRPF funded projects. Although many funding agencies emphasize that their aim is to fund innovative research, PRPF systems might instead be conservative, and favour well-established views rather than radically new ideas (see Nicholson and Ioannidis 2012; and reviews by Guthrie, Ghiga, and Wooding 2018; Guthrie et al. 2019).\n\nThese epistemic problems would be acceptable if the costs and impacts of the system were relatively low. Yet, the costs of PRPF turn out to be very high. Link et al. (2008) show that researchers at R1-universities in the United States spend on average more than four hours a week writing project applications. Similar studies were conducted for the National Health and Medical Research Council, a major funding organization for biomedical sciences in Australia. The results of these studies indicate that the time investment in 2009 was as much as 180 years of research time to fund 620 projects, and by 2013, the costs had gone up to more than 500 years of research time – equivalent to € 41 million in salary – to fund approximately 700 projects with a total value of € 226 million (Herbert et al. 2013).\n\n\n3. Ethical values and norms associated with research integrity\n\nIndividual ethical behaviour co-varies with situational factors and with personality traits (Bruton et al. 2020). Here, we will be concerned with the role of situational factors, and more specifically with how institutional and structural aspects of research environments prompt unethical behaviour. Our focus on systemic incentives fits today’s scholarship on research integrity. For example, in a recent consensus study report of the National Academies of Sciences-Engineering-Medicine (NAS 2017, 208), it is noted that “patterns of funding and organization that have emerged over the past few decades in the United States have created environments increasingly characterized by elements [ …] that are associated with cheating, such as very high stakes, a very low expectation of success, and peer cultures that accept corner cutting” (NAS 2017, 98). We concur, and analyse the characteristics of PRPF that lead to unethical behaviour below. Before doing this, we first identify the core principles of research integrity.\n\nScientists are bound by a number of science-specific norms and values. These norms and values are frequently made explicit in scientific CoCs. Such CoCs are a good starting point for our analysis because they are the result of extended debates among a wide variety of stakeholders. They function as consensus statements, reflecting an overall agreement among these stakeholders about the norms that should guide research, and present both minimal conditions for ethical research practices and aspirations. In addition, institutions and funding agencies often adopt these CoCs as a framework for their own policies and regulations on research integrity.4 Hence, if we can show that PRPF threatens the core values of the CoCs, we have a strong case for urging these academic institutions and funders to revise their policies on PRPF.\n\nWe analyzed the following five CoCs: the Singapore Statement on Research Integrity (Resnik and Shamoo 2011) that was written at the second World Conference on Research Integrity, the European Code of Conduct for Research Integrity (2017), developed by the European Science Foundation and All European Academies, Doing Global Science: a guide to responsible conduct in the global research enterprise (IAP 2016) written by a committee of leading scholars on research ethics, Fostering Integrity in Research (NAS 2017), a consensus document published by the National Academy of Sciences, and Ethical Guidelines for Peer Reviewers (COPE 2013), drafted by the Committee on Publication Ethics. These CoCs were selected because of (1) their geographical focus (EU, USA, world), (2) their generality (not about one discipline or aspect, but about science in general), and (3) their authoritative status within the scientific community. We also analyzed Ethical Guidelines for Peer Reviewers (COPE 2013), because peer review is central to PRPF.\n\nThe selected CoCs differ somewhat in their definitions of integrity and misconduct. They also vary in their approach. Some CoCs are more value-based, and state which values (e.g. honesty) should guide research. Other CoCs are more norm-based, and primarily indicate which behaviours need to be sanctioned or stimulated (Godecharle, Nemery, and Dierickx 2014). The CoCs also vary with regard to the values and norms they include. This variation is largely due to the inevitable vagueness associated with the formulation of values and norms, and due to the different objectives of the CoCs. Still, the differences do not reflect deep disagreements on what constitutes misconduct or about the core values.\n\nIn order to facilitate our assessment, we have extracted from the CoCs one list of values and norms. This list ignores the subtle differences just mentioned, and captures what the CoCs have in common. Table 1 summarizes how our list maps onto the values prioritized by the various CoCs.\n\nThe CoCs are, in order, the European Code of Conduct for Research Integrity (ECCRI), Doing Global Science (DGS), Fostering Integrity in Research (FIR), the Singapore Statement on Research Integrity (SSRI) and Ethical Guidelines for Peer Reviewers (EGPR).\n\nOur list comprises the following values and norms:\n\n- Accountability entails that scientists should be able to explain and justify their claims and actions.\n\n- Honesty obliges scientists to be accurate, transparent and clear in all their communication. Researchers violate this value when they fabricate or falsify data, when they present findings in a misleading way, and when they are insufficiently open about the uncertainty of their claims.\n\n- Impartiality means that researchers do not let their personal opinions, interests, preferences prejudices or the interests of the bodies commissioning their work influence their decisions and judgements. Rather, researchers’ decisions and judgements should serve the aims of science (e.g., truth, instrumental value).\n\n- Responsibility requires researchers to take into consideration the broad interests of society. Researchers should spend their resources on research that benefits society, that does not violate the ethical guidelines for activities involving human subjects and animals, and that properly mitigates possible harms and risks.\n\n- Fairness implies that scientists should show due respect to everybody they interact with in a scientific context, and sufficiently acknowledge the work of others. This applies to interactions with fellow-scientists, but also to interactions with participants in experiments, the readers of scientific publications, administrative staff, students and funders.\n\nWe acknowledge that alternative categorizations are possible, and that there is some overlap between some of these values (as there is in the CoCs). Still, our categorization fits our purposes, as it helps us (in Section 4) in structuring the ways in which PRPF invites ethically questionable practices.\n\nImportantly, on a final note, in the remainder we will construe the five values of research integrity primarily as ethical values. We acknowledge, though, that each of them is directly or indirectly related to epistemic values. It is no coincidence that this is so: research integrity is concerned with scientific research, and society values such research primarily because of the epistemic goods it delivers. Given this entanglement of ethical and epistemic considerations, our focus on the ethical aspects of PRPFs is inevitably somewhat artificial. However, such a focus is useful here, as it more clearly brings out an important point that has not received due attention: the ethical problems that PRPF systems give rise to.\n\n\n4. PRPF prompts violations of research integrity\n\nThis section argues that PRPF forces or incentivizes researchers to violate each of the five aforementioned values. Many ethically questionable practices can be categorized as a violation of more than one value. When that is the case, we just place and discuss it under one value. Our focus will be on ethical problems that arise for individual researchers who apply for, evaluate and receive research grants. System-level moral issues, such as the inefficiency of PRPF systems, which are primarily associated with policy-makers and funding organizations, fall outside our scope.\n\nBefore we turn to these practices, it is good to note that most of them have not, or only rarely, been studied. We refer to empirical work whenever it exists, but this is unfortunately not the case for all practices. Even though this means that there is not always published evidence that backs up our claims that these practices are prevalent, we believe that most people familiar with academia and its funding processes will recognise the practices we discuss and know how common they are. We too have at some point engaged in some of these practices, and we expect that most readers of this paper also either engage in them or know of colleagues who do.\n\nScientists are bound by the norm of accountability: they should only make claims that are justified to the degree that is appropriate for the context in which they make these claims. As both funding applications and review reports consist in claims about future research, this norm is directly relevant to the way PRPF distributes research funding. We argue that PRPF commonly forces both applicants and reviewers to make claims they cannot sufficiently justify.\n\nFirst, consider applicants. Most grant applications require applicants to develop detailed timelines, and to describe expected milestones, results and applications. However, the outcomes and course of scientific research are notoriously difficult to predict (Carrier 2008; Mallapaty 2018; Sinatra et al. 2016). Indeed, scientists have been quite wrong about the future impact of, among others, Mendelian genetics, Pasteur’s fermentation theory, continental drift, the idea of Australopithecus being ancestral to Homo, the prion theory (concerning the causes of BSE or “mad cow disease”), and bacterial infection as the cause of stomach ulcers (Benda and Engels 2011; Gordon and Poulin 2009). Because making predictions of future success or listing project deliverables is a mandatory part of project applications, researchers are thus forced to make claims that they cannot sufficiently justify. Note that some projects (viz., risky ones) might be subject to this worry more than others. But even the success of allegedly fail-safe projects depends on various factors that are not under the control of the researchers who write the grant applications, including, among others, fluctuations in the supply of qualified labour, political and economic developments, changes in institutional policies, contingencies in the poorly understood process from invention to innovation, and personal and inter-personal issues arising within the project team.\n\nGrant-decision makers (grant committee members and peer reviewers), too, are forced by PRPF to make claims they cannot justify. Note that their decisions require a high degree of justification, as they decide over large amounts of money and their decisions have a great impact on the careers of researchers, the course of science, and the people potentially affected by the outcomes of the proposed research. One reason why it may often be impossible for grant-decision makers to meet the required high degree of justification is that in many funding competitions there are far more high- quality applications than there is money to distribute. Because scientific success is difficult to predict (see above), grant-decision makers lack grounds for choosing between these high-quality applications (Kaplan et al. 2008). Because of this, there is a push to generate unjustified reasons and to overemphasize tiny or even insignificant differences between granted and rejected proposals. Another reason why the required degree of justification is rarely met is that grant-decision makers typically do not get all the relevant information that is needed to make a proper judgment. For example, grant-decision makers are often asked to give scores to applicants but due to differences in experience and context are likely to work with a different reference class (e.g., an applicant might be judged top-5% by one reviewer, but top-20% by another because the reviewers come from different fields). In addition, grant-decision makers often have to evaluate projects that fall outside their direct area of expertise. This is the case, for instance, when they serve in interdisciplinary grant committee panels (Bromham et al. 2016).\n\nIn light of the above, grant-decision makers are forced to make unjustified evaluations. In addition to these forces, there are also various incentives that give rise to violations of accountability. For instance, the large review burden and time-pressure of PRPF may incentivize some reviewers to deliver low-quality reports, and, hence, to make judgments that are insufficiently justified (Publons 2019). Reviewers in grant panels typically have to read thousands of pages of applications, review reports and researcher profiles. Even the most diligent among them are unlikely to have the time to thoroughly read all these materials. This means they either have to skim through projects, or select a few that are closest to their expertise. In this light, it is also no surprise that reviewers admit that irrelevant factors, such as spelling errors, play a role in their grant decisions (Inouye and Fiellin 2005; Porter 2005).\n\nNorms of honesty demand researchers to not intentionally make false claims. Some indirect implications of these norms are that researchers should not withhold crucial information, include irrelevant information, or use other methods of deception. In the context of research funding, this norm is primarily relevant for project proposals and evaluation reports.\n\nFirst, PRPF systems strongly incentivize researchers to violate authorship norms. Because of low success rates, the increasing dependence of academic institutions on external grant acquisition, and the prestige derived from successful applications, scientists are strongly encouraged (or obliged by their institutions) to take part in as many funding competitions as possible (Fang and Casadevall 2016). Because the applicant’s profile plays an important role in the evaluation of grant proposals, senior scientists are most likely to be successful. However, senior scientists rarely have the time to write (many) grant applications. Accordingly, they may be tempted to delegate some or even most of the work of grant writing to their junior staff, and submit the application under their own name. At the same time, there are plenty of funding schemes for which junior researchers (e.g., PhD students, postdocs) are not eligible, even if these schemes are primarily used for funding work carried out by such junior staff (e.g. postdocs and PhDs hired on a project). To the extent that junior researchers contribute to writing such grants, the eligibility criteria of PRPF systems induce them to write applications under a different name. Relatedly, it is a public secret (although how pervasive it is has not been investigated yet) that junior researchers sometimes submit proposals under their own name that they have not written themselves. Grants for junior researchers are then used to pursue the research goals of others (senior researchers, labs). Such practices violate the norm of honesty in that the work of the actual author(s) is not acknowledged, and this for the purpose of deceiving grant-decision makers.\n\nAn incentive to withhold crucial information is the risk that reviewers will steal the ideas of the applicants they are assessing—and there is usually plenty of time for this to happen, given the typically substantive time delay between application and funding decision. Accordingly, it is no surprise that applicants have characterized their own application strategy as follows: “you only show them [reviewers] enough to get it [your project] funded”, otherwise they will “kill your grant, and then take and do it” (interviewee in Anderson et al. 2007a, 425).\n\nAnother salient incentive for PRPF systems to be dishonest relates to so-called ‘grantsmanship’. This term generally refers to the art of writing successful funding applications, but is typically used to single out those aspects of the application that are not scientific but rather formal, stylistic and rhetorical. Indeed, many guides of grantsmanship emphasize that grants are in the first place pieces of advertising (e.g. Koppelman and Holloway 2012; Rasey 1999). Because the review process should primarily evaluate scientific merit (rather than formal or stylistic qualities), grantsmanship adds noise to the evaluation system. Such noise is particularly harmful because funding competitions are a zero-sum game: successful applicants win at the expense of other applicants. Superior grantsmanship may thus push equally good or better applicants below the funding threshold. Because it is unlikely that reviewers are fully insensitive to factors that are unrelated to scientific merit (Inouye and Fiellin 2005; Porter 2005), PRPF systems plausibly reward grantsmanship. This is illustrated by the staggeringly high success rates of some grant writing consultants:5 being supported by people with no background in the proposed research dramatically increases the chances of getting money for that research.\n\nAnother practice that PRPF incentivizes concerns ‘double-dipping’, the practice of submitting the same research project in multiple funding calls without proper acknowledgement. The reasons researchers are incentivized to engage in double-dipping have been mentioned above: low success rates, academic institutions’ increasing dependence on external funding, prestige and so forth. That double-dipping is common is suggested by Garner et al. (2013). In their study of U.S. funding in the biomedical sciences, these authors found that, between 2007 and 2011, over $20 million was allocated to projects that had already attracted funding before. Although this amounted to only a small percentage of the total budget that was distributed, Garner et al. (2013) suggest it probably is an under-estimation, given the difficulties in finding duplicates. In any case, it is research money that cannot be spent on other research projects. Double-dipping includes several dishonest practices, such as, withholding relevant information, self-plagiarism and, plausibly, the use of grant money for purposes other than those for which it was intended.\n\nFinally, PRPF also incentivizes the dishonest practice of applying with research that has already partially been done (Anderson et al. 2007a, 448). In a longitudinal study of grant applications from the Deutsche Forschungsgemeinschaft, Serrano Velarde (2018) observes that decreasing success rates have made applicants increasingly concerned with portraying their research projects as certain to be successful. Arguably, they share this concern with funding agencies, that, in light of the demand for greater public accountability, typically ask applicants to specify clear, demonstrably feasible and measurable targets (deliverables, outputs, milestones) (Frodeman and Briggle 2012). Reviewers, too, seem biased towards success, for they appear to reward projects that are highly likely to achieve what they promise (Inouye and Fiellin 2005). Because of this, portraying an ongoing or finished research project as if it is merely a research plan, is an effective and – according to interviewees in Anderson et al. (2007a) – popular strategy. In that light, it is not surprising that 27% of early-career scientists and 72% of all midcareer scientists in a survey admitted to improper use of funds such as using money from one project in another (Anderson et al. 2007b).\n\nImpartiality means that researchers should aim their decisions and judgements to primarily serve the interests of science. Accordingly, their decisions and judgements should not be led by prejudices, the interests of their sponsors, or any other bias.\n\nThere are at least two senses in which PRPF schemes force researchers to violate norms of impartiality. First, there is solid evidence that the judgements of grant-decision makers are subject to various biases (Boudreau et al. 2016; Guthrie et al. 2019; Nicholson and Ioannidis 2012; van den Besselaar 2012). Thus, at least given the way that PRPF schemes are currently set up, serving as a reviewer presently means engaging in a practice that is known to violate norms of impartiality. Surely, full impartiality is too stringent a demand for many scientific activities—for instance, such a demand would make carrying out research virtually impossible. But in the case of distributing research money, there do exist alternatives that fare much better than PRPF when it comes to impartiality (e.g., lotteries, egalitarian sharing, see Section 5).\n\nA second sense in which PRPF schemes force researchers to transgress norms of impartiality relates to the political context that the schemes operate in. In some cases, grant decision-makers might be requested to take into account such things as the geographical and institutional distribution of the grants they award and the political sensitivities of the governments they work for. Hegde (2009) and Batinti (2016), for instance, found that working in a U.S. presidential swing-voter state or in a state of certain congressional appropriators increases applicants’ likelihood of success up to 10.3%. Grant-decision makers thus seem to be compelled to let the interests of the bodies commissioning their grant reviewing work interfere with their judgment. As a result, projects might get funded that are optimal in political terms, but sub-optimal in scientific terms.\n\nTurning to the incentives to act against the norms of impartiality, the track record of applicants is an important consideration in grant-decision making.6 Together with the pressure to be successful in grant applications, PRPF might thus indirectly invite applicants to engage in practices that boost their publication record (in terms of number of publications, citation counts, or journal impact factors) but fail to serve the interests of science (Bouter 2015; Tijdink, Verbeke, and Smulders 2014). Furthermore, to reduce the workload of grant committee members, many PRPF schemes allow applicants to indicate potential reviewers of their proposal; applicants thus get the opportunity to increase the likelihood of receiving a favourable review (Severin et al. 2019). They can further increase this likelihood by selective citing (e.g., citations of possible reviewers, no citations to hostile reviewers), which, according to a survey with experts on research integrity, occurs relatively frequently (Bouter et al. 2016). Similar incentives to violate the norm of impartiality also arise because, unlike reviewers, grant-decision makers will often come from the same country as applicants. For example, up to two thirds of all panel members for the Flemish Research Council (FWO7; Belgium) can have an appointment at a Belgian University.8 Especially in smaller countries like Belgium, these decision makers often participate in applications of their friends (or enemies) and favourite (or disliked) colleagues. Under these circumstances, cronyism is to be expected (van den Besselaar 2012).\n\nNorms of responsibility require researchers, in their work, to take into account the broad interests of society. This norm is particularly salient in the case of publicly funded research.\n\nBeing responsible to taxpayers implies that the returns of public funding bodies’ investments should be public. However, the 1980 Bayh-Dole Act established a legal framework in the U.S. that encourages recipients of public research money to derive patents from their publicly funded research results (Rai and Sampat 2012). The increasing emphasis that public funding agencies’ place on valorization drives scientists towards research that directly creates economic returns (De Jonge and Louwaars 2009), and to exploit the commercial opportunities created by the Bayh-Dole Act. Proponents of the act (and of academic patenting more generally) point out that academic patenting benefits society because it promotes commercial development of otherwise purely academic knowledge. Their arguments have been repeatedly criticized on empirical and epistemic grounds (Mirowski 2011; Radder 2019; Sterckx 2010). But on whatever side of the debate one stands, academic patenting does push publicly acquired knowledge out of the public domain. So at least in this sense, U.S. funding agencies incentivize practices that go against public interests. The same holds true for funding agencies that work for governments that have adopted (viz., Japan) or are in the process of adopting (viz., the E.U.) Bayh-Dole-type legislation (Lynskey 2006; Mirowski 2011).\n\nAnother worrisome practice that researchers participating in PRPF schemes are strongly encouraged to engage in pertains to hiring. PRPF schemes are by definition project-based, and thus only provide funding for the duration of the project. Accordingly, grantees are pressurized to hire, as project collaborators, cheap temporary staff (PhD students, Postdocs), even if that staff carries out work that, in the long run, would in a more cost-effective way be carried out by specialized, permanent staff. The considerable costs for society do not stop there: the reliance of grantees on temporary labour presumably also contributes to the mismatch between the production of PhDs and the availability of jobs in the academic sector that industrialized societies are currently facing (Gould 2015). Although part of the costs of this mismatch can be compensated for by the training that temporary grants may provide for jobs outside academia, the mismatch probably also exacerbates many questionable research practices (Smaldino and McElreath 2016).\n\nWeaker, but still significant incentives relate to project budgets. For one, various incentives invite applicants to apply for more research money than needed, including minimum and maximum budget clauses in grant applications, a lack of institutionalized differentiation with respect to grant size between resource-intensive and less resource-intensive disciplines (for all of these see e.g. the FWO), and pressure from researchers’ home institutes. Further, funds are typically to be spent within the intended timeframe of the project in question; it is an open secret that many researchers are tempted to use, before the actual end of their project, estimated surpluses for purposes unrelated to the proposed research. As Brennan and Magness (2019) put it in their Cracks in the Ivory Tower: “If we are not rewarded for being frugal, we might as well [...] buy the nicest computers and hotel rooms our budget permits”.\n\nThe value of fairness requires that scientists treat everybody they interact with or affect in their work with due respect. Fairness concerns all interpersonal relationships in science, and in that sense overlaps with the other values on our list. Many of the practices we have already described under the headings of honesty, responsibility and objectivity also constitute a lack of respect for other scientists.\n\nIn addition to these, at least one other violation of fairness deserves mentioning. Most of the incentivized practices we have discussed here are commonly accepted in academia. For example, researchers write guides about grantsmanship (Koppelman and Holloway 2012; Rasey 1999), researchers are often expected to apply for more funding than they can effectively use, and at least at our home institutions the use of grant writing consultants is explicitly encouraged. We know of several postdoctoral researchers who are funded by one grant to allocate more than half of their research time to applying for other lab-level research grants. Such violations of norms of research integrity appear to be tolerated by the scientific community. Indeed, it is unlikely that commissions for research integrity would seriously investigate allegations of misconduct if the misconduct consists merely in grantsmanship or ill-justified timelines in applications. That such ethically questionable practices are tolerated is unfair towards those researchers that do not give in to the pushes of PRPF systems to engage in such practices. Moreover, it is in direct violation of the CoCs, which explicitly warn against tolerating unethical behaviour.\n\n\n5. Discussion and conclusions\n\nThe violations we have listed are not meant to be exhaustive, and they are unlikely to capture all the senses in which PRPF systems prompt ethically questionable research practices. In addition, some may find that most of the questionable research practices we discussed are minor issues, and it is true that none of the problems present a clear knock-down argument against PRPF. Still, we have seen that PRPF systems force or incentivize researchers to violate, in one way or the other, each of the five norms and values commonly associated with research integrity and included by all major CoCs. In fact, our assessment includes many of the ‘cardinal sins’ against research integrity: self-plagiarism (in the form of double-dipping), taking credit for someone else’s work (in cases where junior researchers write applications for their senior colleagues) and, potentially, falsification and fabrication (in cases where scientific results are adjusted to conform to promises made in the grant application). Listing these violations side by side shows that ignoring these problems comes at a substantial ethical cost, as the issues are numerous, pervasive and unlikely to disappear on their own. In this concluding section, we briefly consider three options for reform.\n\nThe first option is to mitigate the perverse incentives associated with PRPF by eliminating or modifying those features of PRPF that prompt questionable behaviour. For instance, funding agencies could remove the demand to formulate strict timelines that indicate expected successes and measurable targets (e.g., number of papers, targeted journals, milestones). While doing so would undoubtedly solve some of the issues we have discussed, this option will presumably remain sub-optimal. To start, many of the features of PRPF were introduced for good reasons. For example, measurable targets make it easier for reviewers to evaluate the output of the project. Second, the likely impact of some of the changes would be limited. If a funding body no longer required applicants to formulate milestones, applicants would arguably continue mentioning them, because they intuit that milestones strengthen their application. Third, some of the incentives we have discussed seem to be intrinsic to PRPF systems and cannot be substantively modified without abandoning PRPF altogether. For instance, as long as grant decision-makers are human, the norm of impartiality will be hard to conform to.\n\nA second option is to draft regulations for the specific context of PRPF— a ‘CoC for grant writing and reviewing’—and to implement mechanisms for the enforcement of those regulations. Some funding agencies have already set steps in this direction. The Flemish and Dutch research councils, for example, require applicants in many of its funding schemes to indicate whether they have submitted or plan to submit their proposal with other funding agencies. It remains to be seen whether such measures will effectively reduce the prevalence of the practices that they target, such as double dipping. But, in any case, it is doubtful that regulatory work will be enough to address all the worries that we have raised. Indeed, as we have seen, PRPF systems are still subject to cronyism, in spite of codes of conduct that explicitly disapprove of cronyism (van den Besselaar 2012).\n\nA final, more radical option is to put into effect alternative allocation systems. Various such systems have been proposed, primarily with the aim of addressing the epistemic shortcomings of PRPF (Guthrie 2019). These alternatives include peer-to-peer distribution (Bollen et al. 2017), allocation on the basis of past performance (Bolli 2014; Roy 1985), a (modified) lottery among short project proposals (Fang and Casadevall 2016), and baseline funding (Vaesen and Katzav 2017). Of these alternatives, allocation on the basis of past performance and peer-to-peer distribution have most in common with PRPF and, accordingly, are most likely to share its shortcomings. The two other alternatives, i.e. lottery-based systems and baseline funding, seem more promising with respect to research integrity. While they might suffer from different (unforeseen) moral problems, they seem less sensitive to many of the issues discussed in this paper. This is because they differ from PRPF in three crucial respects.\n\nFirst, baseline funding and lottery-based systems substantively minimize reliance on judgements that we have seen to be problematic. These judgements include unjustifiable predictions in applications and review reports (violation of accountability), omitting crucial methodological details in project proposals (violation of honesty), and biased grant evaluations (violation of impartiality).\n\nSecond, baseline and lottery-based systems are relatively difficult to game. This is because they disregard many of the allegedly salient, but easily manipulated, differences among applicants that PRPF grant decisions are informed by. For instance, baseline and lottery-based systems are largely immune to grantsmanship and do not reward the many questionable practices that applicants might use to pimp their publication track record (e.g., salami-slicing, cutting corners, plagiarism, not publishing negative results).\n\nFinally, the credit and prestige that applicants derive from a baseline or lottery-based grant would, relative to the credit and prestige derived from a PRPF grant, be minor or even nil. Indeed, there is little merit in acquiring a grant based on chance (lottery-based) or when every researcher gets one (baseline funding). An additional benefit of decoupling (alleged) merit and funding is that it would temper the Matthew effect and the overconfidence associated with repeated success in PRPF competitions. A non-merit based system would promote intellectual humility, a value that is both epistemically and ethically desirable (Alfano, Tanesini, and Lynch 2020).\n\nA way to summarize these three differences between PRPF and the two alternatives is that only the former distributes funding on the basis of competition between researchers. In various ways, the competition for funding incentivizes researchers to cut corners and violate generally accepted norms of research integrity. This is interesting, as competition also seems to incentivize researchers to violate CoCs in other parts of science such as the research process and journal publications (Anderson et al. 2007a; Fang and Casadevall 2015; Fanelli 2010; Tijdink, Verbeke, and Smulders 2014). Our paper thus adds to these existing arguments for making science and its funding less competitive. Moreover, given PRPF’s epistemic shortcomings, and the likely epistemic advantages of baseline and lottery-based funding, there are also non-ethical reasons to take these alternative systems seriously.\n\n\nData availability\n\nNo data are associated with this article.",
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PubMed Abstract | Publisher Full Text | Free Full Text\n\n\nFootnotes\n\n1 Throughout this paper, we use the term ‘science’ to refer to all academic disciplines.\n\n2 These numbers are for 2020, see https://www.nih.gov/grants-funding and https://www.nsf.gov/about/glance.jsp\n\n3 https://www.forschung-und-lehre.de/wie-gestalte-ich-zielvereinbarungen-313/\n\n4 See e.g. the list of stakeholders in the European Code of Conduct for Research Integrity (2017).\n\n5 These success rates are advertised on the websites of grant writing consultants. We do not refer to specific websites here, because we think some of their practices are unethical.\n\n6 See e.g. ERC (https://ec.europa.eu/research/participants/data/ref/h2020/wp/2018-2020/erc/h2020-wp18-erc_en.pdf#page=34) and NSF (https://www.nsf.gov/pubs/policydocs/pappg18_1/pappg_3.jsp#IIIA2a).\n\n7 https://www.fwo.be/en/fellowships-funding/research-projects/junior-and-senior-research-projects/\n\n8 https://www.fwo.be/nl/het-fwo/organisatie/fwo-expertpanels/reglement-fwo-interne-en-externe-peer-review/"
}
|
[
{
"id": "99418",
"date": "12 Nov 2021",
"name": "Lambros Roumbanis",
"expertise": [
"Reviewer Expertise Sociology of Science",
"Science and Technology studies (STS)",
"Evaluation studies",
"Theory of Science",
"Sociology of Judgment and Decision-making."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments by Roumbanis to Conix, De Block and Vaesen (2021) “Grant writing and grant peer review as questionable research practices”\nThe critical approach that you have chosen for the present paper provides the reader with a good picture of what really is at stake in grant peer review. By demonstrating how the system of competitive funding prompts ethically questionable behaviors and opportunistic strategies, I believe you hit one of the two Achilles heels of the allocation system, the ethical (the other being the epistemological). If the distribution of research opportunities within the academic communities not only generates demoralized scholars, but also ethically questionable practices, then this seems to be a case of a “tragedy of the commons.” I truly sympathize with your effort to shed new light on how the incentives of peer-review project funding (PRPF) leads to undesirable social outcomes. Your paper is well-written and perfectly clear in its general line of argumentation. I have, however, four comments that I would like to share. Hopefully, you will find them relevant for your ongoing meta-scientific investigation.\n\nFirst, the Mertonian norms of science could be an important starting point for a general discussion about the ethical values that guide or at least ought to guide research. There have been a number of critical responses regarding the validity of Merton’s theoretical claims and some scholars have presented new alternative views. In any case, I interpreted your analysis of the codes of conduct (CoCs) as an implicit elaboration of Merton’s thesis about “the Matthew effects,” which you explicitly mention in the paper. In that sense, I believe your investigation makes a fine contribution to the ongoing dialogues within modern sociology of science. Yet my point is, that perhaps you should relate more explicitly to Merton for reasons of contextualization. Your study may also benefit theoretically if you dig deeper into these discussions (see e.g., Knuuttila 2012; Bielinski and Tomczynska 2019; Grundmann 2013; Stehr 2018). As I see it, when reading Merton’s own work, there certainly exists a tension between the “ethos of science” and the “organization of science” – a tension between the ideals and the realities of modern science. You show in your study how the ethos of science has been violated by the current competitive funding regimes in a way that adds a new problematic dimension to scientific progress.\nFrom a retrospective analysis, Serrano Velarde (2018) demonstrated how “the way we ask for money” have changed dramatically over the past hundred years in Germany. She illustrates this change in her study about the institutionalization of grant writing practices by showing a picture of Noble laureate in medicine Otto Warburg’s application from 1921, which contains only one short sentence saying “Ich benötige 10 000 (zehntausend) Mark” (in English: “I need 10.000 Mark”). This is a remarkable contrast with how a proposal must be composed today to have a chance of being funded.\n\n(Fig.1 from Serrano Velarde 2018, p.90)\nSecond, when I read your analysis of the scientific codes of conducts (CoCs), I was a bit surprised by the absence of concepts like solidarity and generosity, especially regarding the issue of “greedy researchers” that apply for (and receives) more funding than they really need. Why do the rules of the funding system allow researchers to get their hands on several grants at the same time? As we know, researchers do not only need to have talent and the right kind of merits, they also need valuable connections and luck in order to succeed professionally. Here, one could possibly argue for the importance of solidarity as fairness from a modified Rawlsian framework, and thereby view generosity as a fundamental virtue for a future ethics of research funding. No matter who we are as researchers or what we have achieved at a certain point, solidarity and generosity always ought to rule. There will always be competition and disagreements between scholars, this is unavoidable; yet we should try to replace the disastrous competition for economic survival in academic science, “the war of all against all” (bellum omnium contra omnes) with the traditional Greek ethical ideal of an honest “friendly rivalry” (ευγενής άμιλλα). Furthermore, if we seriously consider using another type of distribution mechanism than peer review (e.g., lottery or baseline funding), then our view of what we regard as just and fair in science, should perhaps also include the two aforementioned concepts. Now, I know that you acknowledged the possibility of alternative categorizations in your paper, and I agree that there must be overlaps between some of the values involved. For sure, the same thing goes for solidarity and generosity in relation to honesty, impartiality, responsibility and fairness.\nThird, relying on recommendations based on Artificial Intelligence (AI) could also be mentioned as a radical proposal for allocating resources. Highly sophisticated and well-designed AI system with the capacity to evaluate a large number of different academic merits and values, identify promising patterns and probabilities for scientific breakthroughs, without the influence of human biases, could perhaps be a more rational and fair method in the future. Obviously, this kind of proposal needs to be properly scrutinized from an ethics of AI perspective – the risks of instead introducing algorithmic biases and discriminatory treatment in academic science must be seriously considered and tested before AI can be implemented as a decision-making technology. Still, you might want to mention AI in your paper together with lotteries and baseline funding as new possible alternatives to traditional peer review.\nFinally, you analyze both the virtues and vices of the current funding regime. However, other important socio-ethical dilemmas that I myself have been thinking about are, for example, organizational side-effect like symbolic violence. In an observational study that I conducted some years ago (Roumbanis 2019) I analyzed the subtle form of power that senior faculty members sometimes tend to exercise on junior scholars when they hold lectures on grant writing and “the art of getting funding”. The issue of researchers having to navigate in relation to different “academic value spheres” (Ekman 2017) also demonstrates how difficult it can be for researchers to embody the codes of conduct, especially for junior scholars to avoid opportunistic actions in precarious situations. These studies, I believe, fits rather well with your own main narrative in the present paper. In addition, the issue of hypocrisy, generated in contemporary organizations partly because of the increasing number of conflicting demands and expectations, could also be taken into account here (Brunsson 2019). Both symbolic violence and hypocrisy could in fact be part of a general description of the problematic side-effects of the organization and culture of the current system of peer-review project funding.\nTo conclude: this is an inspiring and interesting paper about the ethical dilemmas in the funding system that currently dominates in most OECD countries. You have indeed highlighted some of the most notorious problems that many of us are witnessing today in academic science. In my view, this is a subject that deserves and is in great need, of further investigation in the increasingly complex research landscape. A small suggestion would be to put the word “ethically” in the title, that is, “Grant writing and grant peer review as ethically questionable research practices.”\nSincerely, Lambros\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": "7517",
"date": "24 Dec 2021",
"name": "Stijn Conix",
"role": "Author Response",
"response": "Thanks for reading our paper, and for your insightful and charitable comments! They illustrate that there is far more to be said about this topic than we managed to cover in this paper. We’ve made various changes on the basis of your comments, and think they have improved the paper. We respond to your comments point by point below. REVIEWER: First, the Mertonian norms of science could be an important starting point for a general discussion about the ethical values that guide or at least ought to guide research. There have been a number of critical responses regarding the validity of Merton’s theoretical claims and some scholars have presented new alternative views. In any case, I interpreted your analysis of the codes of conduct (CoCs) as an implicit elaboration of Merton’s thesis about “the Matthew effects,” which you explicitly mention in the paper. In that sense, I believe your investigation makes a fine contribution to the ongoing dialogues within modern sociology of science. Yet my point is, that perhaps you should relate more explicitly to Merton for reasons of contextualization. Your study may also benefit theoretically if you dig deeper into these discussions (see e.g., Knuuttila 2012; Bielinski and Tomczynska 2019; Grundmann 2013; Stehr 2018). As I see it, when reading Merton’s own work, there certainly exists a tension between the “ethos of science” and the “organization of science” – a tension between the ideals and the realities of modern science. You show in your study how the ethos of science has been violated by the current competitive funding regimes in a way that adds a new problematic dimension to scientific progress. From a retrospective analysis, Serrano Velarde (2018) demonstrated how “the way we ask for money” have changed dramatically over the past hundred years in Germany. She illustrates this change in her study about the institutionalization of grant writing practices by showing a picture of Noble laureate in medicine Otto Warburg’s application from 1921, which contains only one short sentence saying “Ich benötige 10 000 (zehntausend) Mark” (in English: “I need 10.000 Mark”). This is a remarkable contrast with how a proposal must be composed today to have a chance of being funded. We now acknowledge in the paper that CoCs are typically based on Merton’s regulative ideals. And we have added that: “This is not to say that the Mertonian norms haven’t been criticized (See Knuuttila 2012 for an overview). For one, there seems to be a disconnect between the norms and actual scientific practice, especially in the context of commodified science. In this sense, the ethos of science conflicts with the organization of science. In fact, our arguments about PRPF illustrate that the organization of science indeed is difficult to bring into accord with the regulative ideals formulated by Merton.” REVIEWER: Second, when I read your analysis of the scientific codes of conducts (CoCs), I was a bit surprised by the absence of concepts like solidarity and generosity, especially regarding the issue of “greedy researchers” that apply for (and receives) more funding than they really need. Why do the rules of the funding system allow researchers to get their hands on several grants at the same time? As we know, researchers do not only need to have talent and the right kind of merits, they also need valuable connections and luck in order to succeed professionally. Here, one could possibly argue for the importance of solidarity as fairness from a modified Rawlsian framework, and thereby view generosity as a fundamental virtue for a future ethics of research funding. No matter who we are as researchers or what we have achieved at a certain point, solidarity and generosity always ought to rule. There will always be competition and disagreements between scholars, this is unavoidable; yet we should try to replace the disastrous competition for economic survival in academic science, “the war of all against all” (bellum omnium contra omnes) with the traditional Greek ethical ideal of an honest “friendly rivalry” (ευγενής άμιλλα). Furthermore, if we seriously consider using another type of distribution mechanism than peer review (e.g., lottery or baseline funding), then our view of what we regard as just and fair in science, should perhaps also include the two aforementioned concepts. Now, I know that you acknowledged the possibility of alternative categorizations in your paper, and I agree that there must be overlaps between some of the values involved. For sure, the same thing goes for solidarity and generosity in relation to honesty, impartiality, responsibility and fairness. We agree that a classification of values/norms that includes generosity and/or solidarity would have made a lot of sense, and now mention these two norms as good alternatives to our classification where we motivate our choice of categories (at the end of section 3). By explicitly mentioning them, we hope to increase the chance that any future work on the ethics of research funding considers them explicitly. As you also mention, the choice of categories is a bit arbitrary, and we think that what matters most in our paper is that we find a sensible home for all the morally problematic behaviors relating to research funding. To avoid having to drastically change the paper structure, we have therefore kept the classification of norms the same as it was before. Overfunding and missing the funding sweet spot are clearly transgressions of norms like generosity and solidarity, but we think that these behaviours can also be framed as violations of responsibility, fairness and honesty. REVIEWER: Third, relying on recommendations based on Artificial Intelligence (AI) could also be mentioned as a radical proposal for allocating resources. Highly sophisticated and well-designed AI system with the capacity to evaluate a large number of different academic merits and values, identify promising patterns and probabilities for scientific breakthroughs, without the influence of human biases, could perhaps be a more rational and fair method in the future. Obviously, this kind of proposal needs to be properly scrutinized from an ethics of AI perspective – the risks of instead introducing algorithmic biases and discriminatory treatment in academic science must be seriously considered and tested before AI can be implemented as a decision-making technology. Still, you might want to mention AI in your paper together with lotteries and baseline funding as new possible alternatives to traditional peer review. This is a good suggestion, thanks! We now briefly mention (in the ‘discussion and conclusions’ section, paragraph starting with ‘A final, more radical option…’) that while at the moment there are no AI-systems that work well enough (and work on this topic is still very scarce, see reference in the paper), this might well be a viable alternative in the future as long as we remain on our guard for possible algorithmic biases. REVIEWER: Finally, you analyze both the virtues and vices of the current funding regime. However, other important socio-ethical dilemmas that I myself have been thinking about are, for example, organizational side-effect like symbolic violence. In an observational study that I conducted some years ago (Roumbanis 2019) I analyzed the subtle form of power that senior faculty members sometimes tend to exercise on junior scholars when they hold lectures on grant writing and “the art of getting funding”. The issue of researchers having to navigate in relation to different “academic value spheres” (Ekman 2017) also demonstrates how difficult it can be for researchers to embody the codes of conduct, especially for junior scholars to avoid opportunistic actions in precarious situations. These studies, I believe, fits rather well with your own main narrative in the present paper. In addition, the issue of hypocrisy, generated in contemporary organizations partly because of the increasing number of conflicting demands and expectations, could also be taken into account here (Brunsson 2019). Both symbolic violence and hypocrisy could in fact be part of a general description of the problematic side-effects of the organization and culture of the current system of peer-review project funding. It is true that both hypocrisy and the kind of symbolic violence that you describe are part of many of the problems that we discuss: many of the practices are common and generally tolerated, and this creates a culture where adhering to codes of conduct is sometimes difficult for particular groups of researchers. Because we think that this problem is particularly pressing for junior scholars, we now mention this in the section on fairness, in the context of tolerating misconduct. REVIEWER: To conclude: this is an inspiring and interesting paper about the ethical dilemmas in the funding system that currently dominates in most OECD countries. You have indeed highlighted some of the most notorious problems that many of us are witnessing today in academic science. In my view, this is a subject that deserves and is in great need, of further investigation in the increasingly complex research landscape. A small suggestion would be to put the word “ethically” in the title, that is, “Grant writing and grant peer review as ethically questionable research practices.” As the other reviewer highlighted that our points are epistemic as well as ethical, we think it better to keep the title as it is, and focus on the point that these practices are problematic."
}
]
},
{
"id": "99420",
"date": "16 Nov 2021",
"name": "Tamarinde Haven",
"expertise": [
"Reviewer Expertise My area of interest is research integrity",
"in addition",
"I have a background in philosophy",
"psychology and 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\nSummary:\nThe authors argue that rather typical behaviours from applicants as well as reviewers in peer-review project funding (PRPF) clash with key values from research integrity codes of conduct (CoCs). After teasing out 5 key values that are shared by a varying set of CoCs, they show for that each value is harmed in the current PRPF system. I find it interesting that the authors focus on questionable research practices by the applicants as well as the reviewers, they present some behaviours that might be familiar to readers, but their interpretation of these behaviours as questionable because they harm the values in CoCs is thought-provoking.\nTo the questions below:\nIs the topic of the opinion article discussed accurately in the context of the current literature?\nThere is an increasing amount of research that investigates questionable research practices, a recent systematic review might provide some points the authors can connect to: Xie, Y., Wang, K., & Kong, Y. (2021). Prevalence of Research Misconduct and Questionable Research Practices: A Systematic Review and Meta-Analysis. Sci Eng Ethics, 27(4), 41.\nAre all factual statements correct and adequately supported by citations?\nWhen the statements are not supported by citations, e.g., p. 5, paragraph 3, the authors acknowledge this, which is normal practice for a philosophical paper.\nAre arguments sufficiently supported by evidence from the published literature?\n\nNot all, but the authors explicitly acknowledge this. That said, their argumentation for this can be substantiated at places, which I point to below.\nAre the conclusions drawn balanced and justified on the basis of the presented arguments?\nMost of the authors’ main conclusions are balanced and justified, but I find part of their concluding statements unjustified. In particular, “In fact, our assessment includes many of the ‘cardinal sins’ against research integrity: self-plagiarism (in the form of double-dipping), taking credit for someone else’s work (in cases where junior researchers write applications for their senior colleagues) and, potentially, falsification and fabrication (in cases where scientific results are adjusted to conform to promises made in the grant application).” p. 8 seems unjustified. The ‘cardinal sins’ indeed include plagiarism, but not *self*-plagiarism, which in various CoC is explicitly separated from plagiarising others, see e.g., Dutch CoC. Taking credit for someone else’s work is guest authorship, which is related to plagiarism but often not considered a cardinal sin. In the article, the authors talk about making claims in grant applications that the grant requesters may not be able to justify, but they don’t go in-depth into the pressure put on researchers *after* having received a grant, where these cases of potential falsification and fabrication should then supposedly happen. Whether the successful applicants do this seems an empirical claim to me, and one that seems rather unlikely.\nSuggestions:\nI have three suggestions. First, a substantial portion of the critique seems focused on the competition that is inherent in peer-review project funding, not so much the peer-review project funding system per se. The competition seems to do the heavy lifting in increasing the likelihood of researchers or reviewers engaging in questionable behaviour (at least for parts of Accountability, Honesty and Impartiality). I am aware that the authors acknowledge how PRPF is a case of organised competition, but it seems to me that PRPF in a situation of medium competition (instead of contemporary excessive competition) would be associated with less questionable behaviour or would at least be a much weaker incentive. It would be helpful to read how the authors see this, because the topic of competition has been discussed by various research integrity scholars (a great example is the paper by Anderson and colleagues from 2007).\nMy second suggestion is that although the authors acknowledge the inevitable overlap of epistemic and moral norms, the harm resulting from the questionable behaviours (QRPs) described seems primarily epistemic. I wonder why the authors hold on to framing their arguments as moral, and not classify some as epistemic (and hence directly supplementing existing epistemic work) and some as moral (opening a new avenue of critique)? It seemed to me that the harm to fairness (unfair of the community to tolerate some of the QRPs discussed because it puts those who do not engage in these QRPs at a disadvantage) is the only harm that seems to have no substantial epistemic component.\nThird, and perhaps obvious, it seems to me that some of these practices are only questionable if *not* disclosed, e.g., for Accountability, these detailed timelines are developed (I presume) to the best of the applicant’s ability, and if the applicant is successful, they need to be adjusted (perhaps in consultation with the funder) when unforeseen circumstances happen, or things otherwise turn out differently. Double-dipping is also a practice that need not be harmful, provided it is acknowledged to the funder.\nSmaller remarks:\n\n“Since low reliability implies low validity,” (p. 3) is not correct, it could be the other way around, but I believe the rest of the sentences then don't hold anymore or need some revisions.\n\n“These epistemic problems would be acceptable if the costs… were relatively low.” seems odd to me, I think the scientific community and the public at large should demand a system that gets them the truest possible knowledge and that if you end up with peer review that gets you non-innovative work and happens by luck only, then the cost aren’t the greatest concern…\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? Yes\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": "7518",
"date": "24 Dec 2021",
"name": "Stijn Conix",
"role": "Author Response",
"response": "Thank you for reviewing the paper, and for your very helpful comments -- they point out some of the issues we had been discussing at length before, and had difficulties resolving. We respond to your comments below. REVIEWER: Is the topic of the opinion article discussed accurately in the context of the current literature? There is an increasing amount of research that investigates questionable research practices, a recent systematic review might provide some points the authors can connect to: Xie, Y., Wang, K., & Kong, Y. (2021). Prevalence of Research Misconduct and Questionable Research Practices: A Systematic Review and Meta-Analysis. Sci Eng Ethics, 27(4), 41. Thank you! As we think this might also be interesting for readers, we’ve added a line and this reference in the first paragraph of the paper. REVIEWER: Are the conclusions drawn balanced and justified on the basis of the presented arguments? Most of the authors’ main conclusions are balanced and justified, but I find part of their concluding statements unjustified. In particular, “In fact, our assessment includes many of the ‘cardinal sins’ against research integrity: self-plagiarism (in the form of double-dipping), taking credit for someone else’s work (in cases where junior researchers write applications for their senior colleagues) and, potentially, falsification and fabrication (in cases where scientific results are adjusted to conform to promises made in the grant application).” p. 8 seems unjustified. The ‘cardinal sins’ indeed include plagiarism, but not *self*-plagiarism, which in various CoC is explicitly separated from plagiarising others, see e.g., Dutch CoC. Taking credit for someone else’s work is guest authorship, which is related to plagiarism but often not considered a cardinal sin. In the article, the authors talk about making claims in grant applications that the grant requesters may not be able to justify, but they don’t go in-depth into the pressure put on researchers *after* having received a grant, where these cases of potential falsification and fabrication should then supposedly happen. Whether the successful applicants do this seems an empirical claim to me, and one that seems rather unlikely. We agree that our statement about the cardinal sins was overstated and not fully justified, and have toned down this part of the paper. We now state (in that same paragraph, start of ‘discussion and conclusions’) that while many of the practices that we discuss may seem like rather minor offenses, some are unquestionably problematic and serious, such as ghost authorship (which we think is more pressing than guest authorship in the context of funding) and double dipping. This is sufficiently strong for the point we want to make. REVIEWER: I have three suggestions. First, a substantial portion of the critique seems focused on the competition that is inherent in peer-review project funding, not so much the peer-review project funding system per se. The competition seems to do the heavy lifting in increasing the likelihood of researchers or reviewers engaging in questionable behaviour (at least for parts of Accountability, Honesty and Impartiality). I am aware that the authors acknowledge how PRPF is a case of organised competition, but it seems to me that PRPF in a situation of medium competition (instead of contemporary excessive competition) would be associated with less questionable behaviour or would at least be a much weaker incentive. It would be helpful to read how the authors see this, because the topic of competition has been discussed by various research integrity scholars (a great example is the paper by Anderson and colleagues from 2007). This is an interesting suggestion. We agree that strong competition is not inherent to PRPF, and that lowering competition (i.e. higher success rates) would lower the incentives to cut corners, and thus might lower some of the problems. However, as long as there is some competition -- which is inevitable in PRPF -- there will be an incentive to engage in some of the practices we discuss. How strong these are is unclear, as it may well be that those who don’t get funding are even worse off than before (for instance because their failing becomes more salient), and might be more likely to engage in questionable research practices. Thus, the precise effect of increasing success rates is hard to predict, and it is far from clear that most of the problems that we discuss would disappear. We therefore decided to focus on the current situation and assess its problems. We do think it is important to mention this point, and now do this in section 2 (second and third paragraphs), where we introduce PRPF. We now clearly state that currently PRPF is highly competitive, and have added an endnote saying that this high level of competition is not inherent to PRPF. REVIEWER: My second suggestion is that although the authors acknowledge the inevitable overlap of epistemic and moral norms, the harm resulting from the questionable behaviours (QRPs) described seems primarily epistemic. I wonder why the authors hold on to framing their arguments as moral, and not classify some as epistemic (and hence directly supplementing existing epistemic work) and some as moral (opening a new avenue of critique)? It seemed to me that the harm to fairness (unfair of the community to tolerate some of the QRPs discussed because it puts those who do not engage in these QRPs at a disadvantage) is the only harm that seems to have no substantial epistemic component. We think that even fairness has a substantial epistemic component (see recent work on the epistemic importance of so-called non-epistemic values, e.g. this paper, and this book chapter), and agree that it is also the case for the other values we discuss. In science, it is difficult to disentangle these two dimensions, and perhaps not always helpful. What matters most is that we highlight issues that have not been recognised before, regardless of whether they are called epistemic or moral. The reason why we explicitly frame them as moral is that, unlike other work on this topic that focuses solely on the epistemic dimension, we start from the fact that these behaviors are violations of codes of conduct. These codes explicitly state that they want to ‘guide researchers in their work as well as in their engagement with the practical, ethical and intellectual challenges inherent in research.’ (see European code of conduct for research integrity cited in the paper). Thus, while clearly also epistemic, these codes claim to have a moral dimension. In addition (but one doesn’t need to buy this to agree with what we state in the paper), we think that many of these behaviours (e.g. not being honest) would be wrong even if they wouldn’t do any epistemic harm. We already had a paragraph on this issue in the paper, and have added a couple of sentences in that paragraph (end of section 3) to make it more explicit. REVIEWER: Third, and perhaps obvious, it seems to me that some of these practices are only questionable if *not* disclosed, e.g., for Accountability, these detailed timelines are developed (I presume) to the best of the applicant’s ability, and if the applicant is successful, they need to be adjusted (perhaps in consultation with the funder) when unforeseen circumstances happen, or things otherwise turn out differently. Double-dipping is also a practice that need not be harmful, provided it is acknowledged to the funder. We agree that some of the problems can be diminished or removed by proper disclosure methods. However, even if it solves or alleviates some problems, it leaves many other problems unaddressed. In addition, we worry that for some problems proper disclosure methods are difficult to design. For example, uncertainty about evaluations of reviewers could be disclosed, but there are likely large differences between the ways different reviewers judge and represent their own uncertainty, and there is inevitably meta-uncertainty about their uncertainty. This would make the disclosed uncertainty very difficult to use, and, thus, part of the problem would remain. We do think that this is a valuable suggestion, and have added it to the paragraph on ‘minor changes’ to PRPF (start of the discussion and conclusions section). REVIEWER: “Since low reliability implies low validity,” (p. 3) is not correct, it could be the other way around, but I believe the rest of the sentences then don't hold anymore or need some revisions. This now reads ‘Since low reliability is typically associated with low validity…’ REVIEWER: “These epistemic problems would be acceptable if the costs… were relatively low.” seems odd to me, I think the scientific community and the public at large should demand a system that gets them the truest possible knowledge and that if you end up with peer review that gets you non-innovative work and happens by luck only, then the cost aren’t the greatest concern… We agree that this statement makes a value-judgement that many readers might not share. We’ve toned down the sentence: ‘These epistemic problems might be justifiable if the costs…’"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1126
|
https://f1000research.com/articles/10-1314/v1
|
24 Dec 21
|
{
"type": "Opinion Article",
"title": "Value-based healthcare’s blind spots: call for a dialogue",
"authors": [
"Jan A. Hazelzet",
"Johan Thor",
"Boel Andersson Gäre",
"Jan A.M. Kremer",
"Nico van Weert",
"Carl Savage",
"Glyn Elwyn",
"Johan Thor",
"Boel Andersson Gäre",
"Jan A.M. Kremer",
"Nico van Weert",
"Carl Savage",
"Glyn Elwyn"
],
"abstract": "The value-based healthcare (VBHC) concept was first proposed as a solution to many of the ills of healthcare. Since then, we have seen the term “value” defined, used, confused, and interpreted in multiple ways. While we may disagree that competition based on value will solve healthcare’s complex challenges, value is a concept integral to the future of healthcare. Before VBHC becomes consigned to the long list of quality improvement trends and management fads that have passed through healthcare, we call for a dialogue around the term value and the implications of its different interpretations. The intention is not just to critique, but to facilitate ongoing efforts to substantially improve healthcare in ways that are relevant and sustainable for society at large.",
"keywords": [
"value-based healthcare",
"patient values",
"quality improvement",
"sustainability",
"co-creation",
"co-evaluation"
],
"content": "Introduction\n\nIn the face of expanding needs and demand for healthcare, coupled with rising costs, inequities, and undesirable variation1,2 in healthcare outcomes and care experience, there has been a surge of interest in the idea of value-based healthcare (VBHC) as a solution. Who could argue with adding value to patients and society through our efforts in healthcare? However, things are not that simple when we consider the many ways in which the term is being interpreted and used in practice around the globe.\n\nIn discussions about VBHC, it becomes clear that the word “value” is used in multiple, sometimes overlapping, or even contradictory ways. As pointed out in a recent report by the European Commission,3 many definitions exist, which causes confusion. This lack of consensus leads to misunderstanding between actors who share the same goal of improving care, where these misunderstandings can further entrench differences in perspectives. The aim of this article is to open a dialogue to reconsider VBHC, by clarifying some different lines of thought on the term value and implications of different uses, to facilitate efforts to improve health care systems. We will first consider the idea of values as a conviction or belief that individuals or social groups consider right, good, or desirable. Second, we will consider the term value in an economic sense of optimizing the use of finite resources. We will then illustrate how these two applications of the word value are often used interchangeably when the term VBHC appears. Unclear use of these two very different meanings makes it difficult to progress on how to define, operationalize and measure VBHC. Both meanings are important, but they point to very different concepts and assumptions.\n\nLet’s start with values, broadly and in plural, and then consider patient values in particular. Values are basic convictions among individuals or social groups; what they consider right, good, or desirable and what is most important in life.4,5 They are influenced by background and culture, but also by experiences and life events – including education or professional training. In daily life, values influence individuals’ behaviors, and guide their evaluation of people, choices, and actions. Specific values such as integrity, balance, fairness, or autonomy are brought to the forefront when they are relevant to a particular context. A systematic review of studies6 where patients articulated what they mean by values, found that patients value their autonomy, consider themselves unique and a whole person, they want clinicians who exhibit professionalism, who listen and have empathy. In clinical interactions, people want to be empowered and to work in partnership. Patient preferences can be considered as expressions of those values.\n\nWhen considering professional values, we can think of altruism, equality, capability, but also pleasure or intellectual stimulation. Most professionals eventually become a patient (or a patient’s next of kin), and enough have shared those experiences in writing that has generated its own literature genre.7 Some patients also become healthcare practitioners. As Virchow’s science of medicine has come into better balance with a return of the “art” and “humanity” of medicine as narratives of personal experience are integrated into curricula.\n\nThe same trend can be seen in efforts to design and measure quality and improvement.8 Patient flows should be mapped from patients’ perspectives. Evaluations increasingly attempt to capture patient reported outcomes and experience measures (PROMs and PREMs), and patient-provider consultation frameworks, which create more space for patients to share the health and care experiences, and subsequently demonstrate a greater valuing of these outcomes and experiences by clinicians.9\n\nThis is especially the case when decisions need to be made. Shared decision making (SDM) needs to be focused on the awareness of possible differences in knowledge and experience of the patient in comparison with the healthcare professional versus the unfamiliarity of the professional with the individual patient’s disease burden, lived experiences, experiences of care, values, and preferences.10 These items are part of the discussion during SDM integral to the co-production approach.11 The combination of society’s and individual patient’s values, person-centered care and shared decision-making, leads to the view that healthcare is not a product, but a service, and a service is always co-produced.\n\nFurthermore, possible outcomes of different treatment options can also be part of this discussion. These outcomes consist of a complex combination of clinically reported outcomes (e.g. survival, organ function improvement, recurrence rate, complications, mobility, activities of daily living, etc., and of patient reported outcomes (PROs), e.g. functional status including physical as well as psychological wellbeing, quality of life, social aspects such as return to normal life etc. In a recent Dutch discourse analysis on VBHC12 (see Box 1), even though four different discourses were recognized, the common grounds were related to SDM: outcome information should eventually be used within the consultation room, SDM was perceived as a core element in VBHC, value was redefined as the personal result of a good interaction between healthcare professionals and patients.12\n\nIn 2020 Steinmann12 conducted a discourse analysis on value-based healthcare (VBHC). He explored both the ambiguity and underlying assumptions that shape various interpretations. The analysis was based on document analysis and semi-structured interviews with key-stakeholders. Steinmann described four discourses: (1) a patient empowerment discourse (VBHC is a framework to strengthen the position of patients); (2) a governance discourse (VBHC is a toolkit to incentivize professionals); (3) a professionalism discourse (VBHC is a methodology for healthcare delivery); and (4) a critique discourse (VBHC is a dogma of manufacturability). Despite the different perceptions, the common ground was shared decision-making as the key-component across all discourses. These different discourses, based on deeply rooted presuppositions, shape the different ways in which VBHC is operationalized in practice.\n\n\nValue (in an economic sense)\n\nVBHC was preceded by a very rich quality improvement (QI) science and practice and has integrated a great deal of QI’s learning models. For example, costs were a part of Juran’s cost of quality13 and the clinical value compass.14 VBHC has brought this relationship to the fore as a focus for measurement. With measurement comes the possibility for comparison. This can be with oneself over time, i.e. a historical comparison, or with others. Comparison raises the question of the role competition can have in driving quality. Health outcomes can be assessed in relation to processes of care, what is done to achieve these outcomes, how resources and competencies are used, including costs. In VBHC, costs should cover the full cycle of care, not limited as often is the case now to a care provider organization or certain drugs or interventions. The result of this assessment, i.e. the relationship between the Health Outcomes achieved and the Costs required to attain them, is what we consider to be Value, value for patients and society, but this is not equivalent to patient value or what patients value. Porter and Teisberg state that ‘value is outcomes achieved per dollar spent’ and ‘The goal is “what matters to patients” and “this unites the interests of all actors in the system”’.15\n\nYet, while VBHC as it was originally presented recognized the patient in the complexity of the healthcare system, the line of reasoning did not move much beyond that. Outcomes are clinically defined by medical condition, but neither the aspirations, priorities and preferences of the patient, nor societal goals, are explored. Instead, the focus moves to using the relationship to expose the competitive traits of care givers to drive improvement. The Value concept itself was not new and VBHC was preceded by a very rich QI science and practice and even to the point that one wonders what VBHC adds to the existing QI discipline.\n\nWithin VBHC, (Time-Driven) Activity-Based Costing is the recommended approach, but it has proven challenging to fully implement16 and often, in practice, supports more of the process improvement efforts we recognize as a staple in QI. VBHC assumes competition will lead to better quality, but this may turn out to be more tied to contextualized political ideologies rather than the medical culture of competition between physicians,15 certainly in Europe.\n\nVBHC might be seen as the next in a long series of quality improvement trends, each introduced with a striking regularity as the end-all solution to health systems current ailments. Cataloguing this parade of health management concepts, Walshe illustrated (using the number of publications regarding each concept per year) how each is introduced, gains popularity for 3-5 years, before waning, soon to be replaced.17 The curious thing, he noted, was that each new concept tended to share much content with its predecessors. It might come with a new tool or approach, but is it enough to justify a whole new label and all the fanfare, or is it another example of pseudo-innovation? Part of the explanation is that certain stakeholders have a desire to market new ideas, to attract attention, acclaim, and, perhaps new business. So, is this also the case with the VBHC concept? A review of articles citing Porter’s trendsetting article on VBHC seems to support this claim.18 For example, the idea that the value of healthcare is important can be traced to the early emergence of modern quality improvement theory in healthcare. Even the value equation – i.e. that health outcomes achieved per amount of resource expended – played a central role, but then it was packaged under the term, “The Clinical Value Compass”, which was published alongside guidance on how to enhance value through continuous healthcare improvement.14\n\n\nSeparating the ideas\n\nWe need both person-centered care through co-produced health care service with SDM (values/context-based decisions), and we need to optimize the use of finite resources for societal efficient co-production of user co-designed healthcare also grounded in societal values. We may disagree with the idea that competition based on value will solve healthcare’s cost and quality conundrum. Either way, enhancing the value of healthcare by improving health and other outcomes while reducing the costs for achieving those outcomes remains a key concern for health systems everywhere.19 How to succeed is a core challenge for society and all stakeholders i.e. clinicians, managers, academics, health system leaders, politicians, citizens and (“third-party”) payers. In recent years, patients and their family and friends have increasingly joined forces in the pursuit of better health and healthcare through different forms of co-production.20\n\nAt the heart of these efforts lie the understanding of how health services contribute to better health, and how to improve these services’ ability to do so, drawing on quality improvement theory as developed over most of the 20th century.13,21 Over the past four decades, this theory has been applied, evaluated, and refined specifically in health services.22,23 Key features include:\n\n• a focus on meeting the needs of those individuals and populations for whom health services are intended\n\n• understanding services in terms of processes and, often complex, systems with a shared aim (e.g. to alleviate the burden of illness; improve health and wellbeing)\n\n• managing variation wisely (e.g. by distinguishing random variation from variation due to a distinct cause, and responding accordingly)\n\n• addressing inequity in health (care)\n\n• promoting learning, collaboration, and deliberate experimentation.\n\nClosely linked to managing variation is the practice of measuring health services’ performance, or quality.24 Such measurement can come with different, sometimes even incompatible, motivations and purposes.25 At its best, quality measurement can promote learning and improvement by highlighting particularly good performance, by bringing attention to areas in need of change, and by providing feedback as such change is introduced.26 Of particular concern are the problems caused by attaching performance-based payment to quality metrics, since that inevitably brings a host of problems, including gaming, incomplete or even inaccurate reporting, and adverse selection of patients (to avoid “looking bad” or losing income).27 This is precisely what VBHC in the competition-sense risks leading to. The problem is that the same measurement that can promote learning and improvement typically cannot also be used to determine financial reimbursement. This represents a huge challenge for proponents of VBHC.\n\nQuality, like beauty, may lie in the eye of the beholder. Nevertheless, it can still be useful to articulate some common attributes of high-quality healthcare. In that vein, the US Institute of Medicine famously proposed that health services which successfully alleviate individuals’ burden of illness or injury are: effective, patient-centered, efficient, safe, timely, and equitable.28 One might argue that ‘sustainability’ is valuable to be added to this shortlist. Patient centered services then are: “services planned, delivered, managed, and continuously improved in active partnership with patients and their families to ensure integration of their health and health care goals, preferences, and values. It includes explicit and partnered determination of goals and care options, and it requires ongoing assessment of how care matches patient goals.”29 This patient centered view on healthcare combined with effective, efficient, and safe characteristics, in our opinion, gives a broader basis for a value-based concept. Including timely and equitable and also looking more precisely at long term effects of care brings the item of sustainability as a 7th item in the list of quality determinants. Increasing inequity, as dramatically shown in this recent COVID-19 period, is not easily “fixed”, but should be addressed specifically by all stakeholders involved in healthcare.\n\nThus, it becomes really complicated since the assessment and valuation of the care or of some treatment is of course performed from the perspective of the patient but might be different if ethical and or societal perspectives are also taken into consideration. So, based on partnership encounters between a patient and his/her healthcare professionals, and in harmony with patient and professional values, using outcomes of other patients with similar conditions, a possible value is determined (outcomes vs costs) for the choices to be made. Again, a process of coproduction. During and after the treatment, together with the patient the real value is assessed by measuring clinician-reported outcomes and PROs, as well as process measures and costs, to if necessary, adapt or even change the treatment or the goals, as a form of coproduction leading logically also to co-evaluation.30 Finally, considering outcomes that really matter to patients in light of the resources expended to achieve those outcomes might conflict with societal, ethical considerations. We should not close our eyes for this tension and should also be part of a dialogue we need to have about value and values. A dialogue about what really matters, inequity in this is a value conflict. A dialogue about the most meaningful impact on healthcare, about getting more health out of the health care system. This cannot be achieved through financial competition but invites to a dialogue about better ways to improve health and health care. VBHC certainly holds premise – provided we remember that there are two fundamental ideas nested in the phrase, one of which has been overlooked so far. We need just as much attention to ‘values’ (what matters when we are ill) as we give to economic value (maximum healthcare per unit of cost). More values are at stake, which presents us with complex dilemmas without clear and simple solutions. We call for a dialogue about how best to promote better health and health care in ways that are relevant and sustainable for our societies.\n\n\nData availability\n\nNo data is associated with this article.",
"appendix": "References\n\nFriel S, Marmot M, McMichael AJ, et al.: Global health equity and climate stabilisation: a common agenda. Lancet. 2008; 372(9650): 1677–1683. PubMed Abstract | Publisher Full Text\n\nMcGlynn EA, Asch SM, Adams J, et al.: The quality of health care delivered to adults in the United States. N. Engl. J. Med. 2003; 348(26): 2635–2645. Publisher Full Text\n\nDefining Value in “Valuebased Healthcare”: Report of the Expert Panel on effective ways of investing in Health (EXPH). European Union; 2019. Reference Source\n\nHeinich N: Des valeurs. Une approche sociologique. Gallimard; 2017.\n\nValue: Cambridge Dictionary. Reference Source\n\nBastemeijer CM, Voogt L, van Ewijk JP , et al.: What do patient values and preferences mean? A taxonomy based on a systematic review of qualitative papers. Patient Educ. Couns. 2017; 100(5): 871–881. PubMed Abstract | Publisher Full Text\n\nBallatt J, Campling P, Maloney C: Intelligent Kindness: Rehabilitating the Welfare State. 2nd edition: Using Kindness to Make Teams Work More Effectively. RCPsych/Cambridge University Press; 2020.\n\nEmanuel EJ: Which Country Has the World's Best Health Care?. Public Affairs; 2020.\n\nvan Egdom LSE , Oemrawsingh A, Verweij LM, et al.: Implementing Patient-Reported Outcome Measures in Clinical Breast Cancer Care: A Systematic Review. Value Health. 2019; 22(10): 1197–1226. PubMed Abstract | Publisher Full Text\n\nElwyn G: Shared decision making: What is the work?. Patient Educ. Couns. 2020; 104: 1591–1595. Publisher Full Text\n\nElwyn G, Nelson E, Hager A, et al.: Coproduction: when users define quality. BMJ Qual. Saf. 2020; 29(9): 711–716. PubMed Abstract | Publisher Full Text\n\nSteinmann G, van de Bovenkamp H , de Bont A , et al.: Redefining value: a discourse analysis on value-based health care. BMC Health Serv. Res. 2020; 20(1): 862. PubMed Abstract | Publisher Full Text\n\nJuran JM, Defeo JA: Juran's Quality Handbook: The Complete Guide to Performance Excellence. 6th ed.McGraw-Hill; 2010.\n\nNelson EC, Mohr JJ, Batalden PB, et al.: Improving health care, Part 1: The clinical value compass. Jt. Comm. J. Qual. Improv. 1996; 22(4): 243–258. PubMed Abstract\n\nPorter ME, Teisberg EO: Redefining Healthcare: Creating Value-Based Competition on Results. Harvard Business Review Press; 2006.\n\nKeel G, Savage C, Rafiq M, et al.: Time-driven activity-based costing in health care: A systematic review of the literature. Health Policy. 2017; 121(7): 755–763. PubMed Abstract | Publisher Full Text\n\nWalshe K: Pseudoinnovation: the development and spread of healthcare quality improvement methodologies. Int. J. Qual. Health Care. 2009; 21(3): 153–159. PubMed Abstract | Publisher Full Text\n\nFredriksson JJ, Ebbevi D, Savage C: Pseudo-understanding: an analysis of the dilution of value in healthcare. BMJ Qual. Saf. 2015; 24(7): 451–457. PubMed Abstract | Publisher Full Text\n\nTeljeur C, Moran PS, Walshe S, et al.: Economic evaluation of chronic disease self-management for people with diabetes: a systematic review. Diabet. Med. 2017; 34(8): 1040–1049. PubMed Abstract | Publisher Full Text\n\nBatalden M, Batalden P, Margolis P, et al.: Coproduction of healthcare service. BMJ Qual. Saf. 2016; 25(7): 509–517. PubMed Abstract | Publisher Full Text\n\nDeming WE: Out of the crisis. MIT Press; 1986.\n\nBatalden PB, Stoltz PK: A framework for the continual improvement of health care: building and applying professional and improvement knowledge to test changes in daily work. Jt. Comm. J. Qual. Improv. 1993; 19(10): 424–447; discussion 48–52. PubMed Abstract | Publisher Full Text\n\nBerwick DM: Continuous improvement as an ideal in health care. N. Engl. J. Med. 1989; 320(1): 53–56. PubMed Abstract | Publisher Full Text\n\nPerla RJ, Provost LP, Murray SK: The run chart: a simple analytical tool for learning from variation in healthcare processes. BMJ Qual. Saf. 2011; 20(1): 46–51. PubMed Abstract | Publisher Full Text\n\nSolberg LI, Mosser G, McDonald S: The three faces of performance measurement: improvement, accountability, and research. Jt. Comm. J. Qual. Improv. 1997; 23(3): 135–147. PubMed Abstract\n\nThor J, Peterson A, Lindahl BThe role of quality registries in health care improvement. Jacobsson Ekman GLB, Nordin A, editors. National quality registries in Swedish health care. Stockholm: Karolinska Institutet University Press; 2016; pp. 53–67.\n\nBevan G, Hood C: Have targets improved performance in the English NHS?. BMJ. 2006; 332(7538): 419–422. PubMed Abstract | Publisher Full Text\n\nInstitute of Medicine Committee on Quality of Health Care in A: 2001. Reference Source\n\nFrampton S, Guastello S, Hoy L, et al.: Harnessing Evidence and Experience to Change Culture: A Guiding Framework for Patient and Family Engaged Care.2017. Reference Source\n\nLachman P, Batalden P, Vanhaecht K: A multidimensional quality model: an opportunity for patients, their kin, healthcare providers and professionals to coproduce health. F1000Res. 2021; 9: 1140. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "126154",
"date": "07 Apr 2022",
"name": "Christian von Plessen",
"expertise": [
"Reviewer Expertise Quality improvement",
"patient safety",
"coproduction",
"health services 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\nThank you for inviting me to this dialogue about value-based healthcare.\n\nThe article Value-based healthcare’s blind spots: call for a dialogue problematizes the blurry use of the term ‘value’. It describes consequences for the understanding and use of the concept of Value Based Health Care (VBHC) and it presents some critical points. The authors propose two main definitions of value. First, they discuss values as principles and standards of behavior with examples from patients and professionals. In the same section, they link the term value to patient reported outcome and experience measures, shared decision making, quality improvement as well as coproduction. The authors cite a discourse analysis on VBHC1 that found diverging discourses on VBHC that, however, were bound together on the grounds of shared decision making as a criterion of (good) VBHC.\nSecond, the authors review value in the economic sense. That is ‘[…] outcomes achieved per dollar spent’ as Porter and Teisberg2 have put it. The authors highlight foundations for VBHC in industrial quality improvement, for example Juran3 or the clinical value compass4. Then they outline the VBHC’s use of measurement, comparison and competition among providers. This is followed by a general criticism that VBHC does not consider preferences of patients or societal goals. They further question its assumption that competition improves the quality of health care. The authors also doubt the novelty of VBHC compared to earlier approaches to improving health care. Rather they consider it old wine in new bottles or a pseudo innovation.\nThe third section Separating the ideas opens perspectives for addressing major problems of health care such as cost, unwarranted variation, inequity, and quality. The authors discuss measurement of quality and problems of financial rewards linked to performance on quality metrics in the context of VBHC. Then they describe attributes of high-quality health care. These are the six dimensions of the IOM report from 20015 and they propose adding sustainability as a seventh dimension. The final paragraph describes the complexity of assessing and valuing health care as well as the need to include patient and societal perspectives in evaluating and improving health care in sustainable ways. The authors end with a call for dialogue about how to do all this.\nComments:\nI very much welcome the invitation to this dialogue and I want to applaud the authors for trying to advance the understanding of what constitutes value in health care (and in society) today. This dialogue is important given the number, the urgency and the complexity of the challenges and the multitude of vested interests of different actors and of possible solutions. Going back to the building blocks of understanding, words, seems a good way to start.\nDialogue from Greek διάλογος (dialogos) means conversation. Its roots are διά (dia: through) and λόγος (logos: speech, reason)6. I will start the conversation by a study of words of the term ‘value’ and then ask some questions and make some propositions that hopefully will contribute to further improve the invitation.\nThe authors distinguish ‘value’ and ‘values.’ These words share a root in the Latin ‘valere’ meaning ‘be strong, be of value, be worth’ and interestingly for health care also ‘be well’. Further back, the Proto-Indo-European root *wal- means ‘be strong’. A market-oriented dimension of value appears around 1300 with “price equal to the intrinsic worth of a thing”. In the late 14th century value denotes the \"degree to which something is useful or estimable.\" The meaning of value as ‘social principle’ (or values) appears in the early 20th century. Further technical meanings were added later, for example, value as the relative duration of a musical note, a numerical quantity that is assigned or is determined by calculation or measurement, or the relative lightness or darkness of a color7.\nThe study of words reveals a positive connotation (strong, well) at the root of value/values. Further it illustrates how different understandings emerged. One is the importance of something positive in the absolute, qualitative and immaterial sense, for example, empathy as a health professional value. The other is the quantifiable, countable amount of something in a relative sense, for example, the outcome of a surgical intervention in relation to its cost.\nModern users of the words value and values might feel more attracted to one meaning of the word than to the other. The abovementioned professional value of empathy might appeal to clinicians. The balanced view on outcomes over cost might appeal to payors. Quality improvers might find themselves between these two in wanting to make care more patient centered while respecting the dogma of “what you cannot measure, you cannot improve\" and the value of efficiency.\nThis is only a beginning. To take this reflection further, one could ask questions such as:\nWhat does the two-sidedness of values/value mean for clinical care?\n\nWhat does it mean for quality improvement?\n\nWhat does it mean for health care governance?\n\nWhat does it mean for VBHC?\n\nWhat does it mean for coproduction of healthcare service?\nA dialogue about the meaning of values and value and about their relationship could address questions such as:\nWhat does value mean for patients? For professionals?\n\nWhich values do they share? Which should they talk about?\nApparent consequences of the values-value distinction for quality improvement, for health system reform and coproduction could be reviewed (and mentioned in the introduction to the current editorial).\nGeneral comments on the manuscript:\nFrom reading the title (and the abstract), I expected an editorial about the blind spots of VBHC. Yet, the article is structured as an analysis of the meanings of the words ‘values’ and ‘value.’ It is somewhat difficult to get an overview over the critique of VBHC (the blind spots). A clearer presentation of the purpose of the editorial and a revision of its structure might make it easier for the reader to participate in the proposed dialogue. For example, the article might begin with a presentation of the problem and its causes (lack of agreement on the meaning of words) followed by a presentation of the possible meanings of values and value. The third part might be a presentation of the implications of the confusion of words for VBHC, for quality improvement, for coproduction and for measurement etc. The final part might then present the invitation to a dialogue and propositions on how to make it happen.\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": []
},
{
"id": "139045",
"date": "26 May 2022",
"name": "Roland Bal",
"expertise": [
"Reviewer Expertise Health policy",
"healthcare quality"
],
"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\nAdding values in different ways In their paper, Hazelzet et al. call for a discussion of ‘value’ in relation to the concept of value-based healthcare (VBHC). While this notion has originally been introduced to advance an economic understanding of healthcare, the authors point out that other meanings of value—which they refer to as ‘values’—have also been put forward, including societal and professional ones, in which they built on the discourse analysis of Steinmann et al. on how VBHC has been conceptualised in the Netherlands (Steinmann et al. 20201). Moreover, they show how VBHC is in actuality a continuation of earlier conceptualisations of quality improvement—adding another fad to the already densely populated business-like approaches to quality of care (Arndt and Bigelow, 1998). Interestingly, they also add a 7th dimension to the notion of quality—adding to the 6 earlier defined by the IOM—namely sustainability, thus bringing a temporal dimension to quality discourse.\nAs the authors argue, nobody can argue with the notion that healthcare should add value. The trouble starts when we want to give substance to the notion of value. In the words of political philosopher Michael Walzer, value is a ‘thin concept’, that is, like freedom or democracy, a concept that we can all adhere to (Michael Walzer, 2019. Thick and thin: Moral argument at home and abroad: University of Notre Dame Pres.). Once we start discussing what we mean with the concept of value (or, for that matter, freedom or democracy)—that is, trying to make it ‘thick’—disagreement arises. Not only do substantiations of value differ between people or institutional actors, they also change over time. For this reason, in fields such as valuation studies (Helgesson and Muniesa 20132) and care ethics (Tronto, 2013. Caring democracy: markets, equality, and justice. New York and London: New York University Pres.), values are seen as relational. Values, that is, are not ‘out there’, to be established once and for all, but are emergent properties of social interactions. In this sense, they are indeed, as Hazelzet et al. argue, ‘co-produced’.\nHealthcare, moreover, is full of contradicting values. This is already true for the 6 values defined by the IOM. Efficiency, for example, often clashes with patient-centeredness. But so does safety. In a study on community housing services for people with intellectual disabilities and severe mental illness, we for example showed how patient preferences were often at odds with safety (Heerings et al. 20213). Respecting the autonomy of the patient (another value) in such situations often clashes with notions of hygiene, lifestyle choices, but also becoming under influence of criminals. Whilst an economic ‘solution’ to this would probably be looking for the optimum of the two (or more) conflicting values—seeking to fix them in time—care ethicists would be more interested in the pragmatic, situated, temporal and collective settlements of such value conflicts, focussing on the ways in which actors ‘tinker’ with values.\nThe relational perspective on values also has consequences for the role of numbers and measurements in healthcare. The economic version of values, as expressed in VBHC, gives them a huge role. Numbers should give as objective as possible representations of states of quality of care, of patient preferences and of costs. Of course, this then brings many discussions about how such measurements should be performed, what the ‘right’ indicators are, how ‘costs’ can be bounded, etc. And it brings huge investments in actual measurements to deliver all this data necessary for the machinery of VBHC to function—and thus its own market. From a relation perspective numbers do not have a representational function but a performative one. That is, they are agents of change. Measurement guides our understanding of an issue or event and when institutionalized often comes to stand for those issues or events. But measurements and data are also used in a situated manner. E.g. patients might use the PRE/OM scores to focus attention on specific issues; doctors might use scores for getting the ‘right’ medication for their patients; regulators use measurements for steering organizations in specific direction (Wallenburg, Essén, and Bal, 20214). Such a relation understanding moreover shows how quantitative and qualitative data can be used alongside, as they are both directed at getting an understanding of the situation and thus serve as reflective tools to enable actors to learn. Strengthening these reflexive capacities then becomes more important than ‘getting the numbers right’.\nOne of the interesting aspects of VBHC is that is has put renewed emphasis on integrated care (not that this wasn’t already done by others of course—there is a whole field of integrated care research), including a reframing of quality and costs as emerging properties of a network rather than characteristics of a single organization. Most (economic) research still takes place at the organizational level though, arguing for example that concentration leads to better and more efficient care, without looking at what happens in the whole system, including the places that are now deprived of specific specialty services. Reframing towards governing healthcare (costs and quality) at a population or regional level then becomes necessary as this allows to take into account the effects of changes in one place on others. It also allows for a better planning of services, instead of letting ‘the market’ (which does not exist in healthcare as it is highly regulated) fix it. Again, relational perspectives here come into play in the sense that they put an emphasis on equity and justice when it comes to governing healthcare and thus adding values such as plurality and solidarity to the value-conundrum (Tronto 2013. Caring democracy: markets, equality, and justice. New York and London: New York University Pres.). Such a reframing towards population or regional levels also shows the complexities involved as interventions in one area might have (unintended) effects on others; effects moreover that are often unpredictable. This then also leads to the necessity of other types of research to evaluate interventions (Greenhalgh et al. 20175).\nAmongst many other things, COVID-19 has shown us that as societies we are prepared to invest in our health almost without limits. Though healthcare might have boundaries, it is unclear where they are. In my country, the Netherlands, boundaries of care are more and more seen not as a cost issue but as an issue of workforce. There simply are not enough people to accommodate the increasing demand for care. This means we have to rethink our approach to governing healthcare, including questions such as what quality can be attained, where healthcare should be placed, what role patients and informal carers have in healthcare and how different professional groups and care providers can collaborate; we also have to rethink the relation between health care and other public services such as housing, education, work. And we have to rethink healthcare in relation to global developments such as climate change and migration (Wagenaar and Prainsack, 2021. The pandemic within. policy making for a better world. Bristol: Policy Pres.). VBHC is not particularly well suited for such challenges. We should be thinking about adding values in different ways.\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? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1314
|
https://f1000research.com/articles/10-1093/v1
|
27 Oct 21
|
{
"type": "Research Article",
"title": "Antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro oral biofilm",
"authors": [
"Pablo Alejandro Millones-Gómez",
"Lidia Yileng Tay Chu Jon",
"Dora Jesús Maurtua Torres",
"Reyma Evelyn Bacilio Amaranto",
"Ingrit Elida Collantes Díaz",
"Carlos Alberto Minchón Medina",
"Lidia Yileng Tay Chu Jon",
"Dora Jesús Maurtua Torres",
"Reyma Evelyn Bacilio Amaranto",
"Ingrit Elida Collantes Díaz",
"Carlos Alberto Minchón Medina"
],
"abstract": "Background: Natural products with antibacterial potential have begun to be tested on biofilm models, bringing us closer to understanding the response generated by the complex microbial ecosystems of the oral cavity. The objective of this study was to evaluate the antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro biofilm of Streptococcus gordonii and Fusobacterium nucleatum. Methods: The experimental work involved a consecutive, in vitro, longitudinal, and double-blinded study design. Propolis samples were collected from 13 different regions of the Peruvian Andes. The disk diffusion method was used for the antimicrobial susceptibility test. The cytotoxic effect of propolis on human gingival fibroblasts was determined by cell viability method using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and the effect of propolis on the biofilm was evaluated by confocal microscopy and polymerase chain reaction (PCR). Results: The 0.78 mg/mL and 1.563 mg/mL concentrations of the methanolic fraction of the chloroform residue of Oxapampa propolis showed effects on biofilm thickness and the copy numbers of the srtA gene of S. gordonii and the radD gene of F. nucleatum at 48 and 120 hours, and chromatography (UV, λ 280 nm) identified rhamnocitrin, isorhamnetin, apigenin, kaempferol, diosmetin, acacetin, glycerol, and chrysoeriol. Conclusions: Of the 13 propolis evaluated, it was found that only the methanolic fraction of Oxapampa propolis showed antibacterial and antibiofilm effects without causing damage to human gingival fibroblasts. Likewise, when evaluating the chemical composition of this fraction, eight flavonoids were identified.",
"keywords": [
"oral biofilm",
"propolis",
"antibacterial",
"antibiofilm",
"chemical compositions"
],
"content": "Introduction\n\nFusobacterium nucleatum (Choi et al., 2020; Geng et al., 2018) and Streptococcus gordonii (Geng et al., 2018) are some of the most important bacteria in periodontal and peri-implant disease, especially in patients who are smokers (Lazar et al., 2015). The scientific community has made considerable efforts to discover new antimicrobial agents that can disrupt the complex structures of subgingival biofilms. One of the main sources of new molecules with antimicrobial activity is products of natural origin (Arbia et al., 2017; Lee et al., 2017; Slobodníková et al., 2016). The search for new antimicrobial agents has gained momentum, particularly due to increased rates of antibiotic resistance to periodontal pathogens (Kouidhi et al., 2015; Rams et al., 2014; Van Winkelhoff et al., 2005).\n\nSocransky et al. (1988) found that the subgingival microbiota can be classified into different complexes based on the association of different microbial species with healthy or diseased sites. If left intact, gingival biofilms create conditions that can favour colonization by orange-complex species, namely, Fusobacterium, Campylobacter, Prevotella, Parvimonas, and some Streptococcus species (for example, S. constellatus). The orange complex is associated with the transition from health to disease due to a change in environmental conditions that favours colonization by Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, which are red-complex species that are considered the main pathogens in periodontal disease (Socransky et al., 1988).\n\nPropolis is a resinous mixture obtained by bees from tree buds, sap exudates or other plant sources and then processed in the hive as a sealant for small holes (Bueno-Silva et al., 2017; Santos et al., 2019). Propolis has been considered a promising source of bioactive molecules with pharmacological properties, including antimicrobial (Alencar et al., 2007; Bueno-Silva et al., 2013, 2015, 2016; Dantas Silva et al., 2017), anti-inflammatory (Markiewicz-Żukowska et al., 2012; Trusheva et al., 2004), antioxidant, and antiparasitic activities (Bueno-Silva et al., 2015). Propolis can have different geographical origins (Freires et al., 2016; Lotti et al., 2010; Piccinelli et al., 2011), and although they may share similar physical characteristics, the chemical compositions of propolis isolates from different sites cannot be the same because the composition depends on the place, time, method of collection, and plants of origin (Becerra et al., 2019). The chemical composition of propolis is closely related to the resins and balsams of the plant sources used to produce it. More than 300 chemical components of propolis have been identified (Barbosa Bezerra et al., 2017; Bryan et al., 2016), and the main groups are waxes, polyphenols (phenolic acids, flavonoids), and terpenoids (Bonamigo et al., 2017; De Freitas et al., 2018; El-Guendouz et al., 2018; Hochheim et al., 2020; Popova et al., 2015; Svečnjak et al., 2020; Touzani et al., 2019; Zhang et al., 2017).\n\nSome research studies have demonstrated an effect of propolis on oral bacteria biofilms. Veloz et al. (2019a) compared some biological properties of individual compounds and mixtures of these compounds from Chilean propolis, such as their antimicrobial and antibiofilm activities against S. mutans cultures. Their results suggest that the polyphenols pinocembrin and apigenin exhibit antimicrobial activity against S. mutans at low concentrations. Martins et al. (2019) evaluated the antibacterial activity, antibiotic effect, and cytotoxic potential of mouthwashes containing Brazilian red propolis in vitro. The results showed that red propolis mouthwashes decreased viable cells to 44% after 1 minute of contact with fibroblasts. Thus, red propolis extract was concluded to exhibit antibacterial activity against Streptococcus spp. and Lactobacillus casei and had cytotoxic and antibiofilm effects similar to those of chlorhexidine.\n\nThe diverse chemical compositions of propolis reflect its advantage as an antibacterial agent (Abbasi et al., 2018; Almuhayawi, 2020; Asawahame et al., 2015; Cardoso et al., 2016; Chen et al., 2018; Lupatini et al., 2016; Martins et al., 2018; Oryan et al., 2018; Pasupuleti et al., 2017; Przybyłek & Karpiński, 2019; Utispan et al., 2017; Veiga et al., 2017; Veloz et al., 2019b; Zabaiou et al., 2017). Despite efforts to investigate its pharmacological properties, no studies have evaluated the action of Peruvian propolis on bacteria present in periodontal biofilms. Therefore, this study aimed to evaluate the antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro oral biofilm of S. gordonii and F. nucleatum.\n\n\nMethods\n\nThe experimental work involved a consecutive, in vitro, longitudinal, and double-blinded study design. The decision criteria method was used for the present investigation (Andersen et al., 2019; Bentz et al., 2013). Based on the results obtained in each experiment, it was decided to continue the trials only with those propolis that showed antibacterial activity, antibiofilm and were not cytotoxic to gingival fibroblasts.\n\nThe propolis samples were collected from fixed apiaries and wild flora around beehives. The collection process was performed by scraping the boxes with a bevelled plastic spatula and placing them in airtight glass containers covered with dark plastic bags until they were delivered to the Biopolymers and Metallopharmaceuticals Research Laboratory (LIBIPMET) of the National Engineering University, Lima. All propolis were masked by a person not involved in the study and labelled with letters until after data processing was completed. They were then stored refrigerated at 4 °C until processing.\n\nSamples were collected in 13 Andean regions of Peru, considered as static apiaries (they are not mobilized by seasonal changes) (Table 1).\n\nThe 13 samples were removed from refrigeration, and after waiting two hours for them to reach room temperature (RT), they were thinly cut and then macerated in absolute ethanol using a volume of 100 mL per 10 grams of propolis. The samples were then incubated at RT for 24 hours. The macerate was filtered using a glass funnel with a 20-cm diameter and sterile cotton, and the sample was collected in a glass dish that was transferred to an extraction hood for evaporation of the ethanol (until a paste was formed) (Markiewicz-Żukowska et al., 2012).\n\nThe crude extract (CE) was solubilized with a mixture of chloroform (CHCl3):methanol (4:1 v:v). Approximately 50 mL of the mixture was needed to completely solubilize each sample. Next, 30 mL of ultrapure water was added to the assembled separation column, followed by solubilized propolis and approximately 250 mL of CHCl3. The separation column was left for six hours until both phases were translucent. We added 250 mL of CHCl3 and repeated the previous procedure. The chloroform phases were combined in the same beaker. The aqueous phase was recovered in a 100-mL beaker. Both collected phases were taken to the extraction hood for chloroform evaporation (Eldeniz et al., 2007; Santos et al., 2002; Verma et al., 2018).\n\nIn the same assembled separation column as above, 300 mL of 1-butanol (BuOH) was added, and then the aqueous phase obtained above was poured into the column. The formation of two phases (lower aqueous and upper butanolic) was observed. They were allowed to stand for approximately three hours until both phases were completely translucent. Then, both phases were separated and collected in beakers of 500 mL (butanolic phase) and 100 mL (aqueous phase). They were immediately transferred to the extraction hood for the evaporation of the BuOH. Once a paste had formed, 50 mL of water was added. Each sample was frozen at −70 °C for 24 hours and lyophilized twice. The aqueous phase was frozen at −70 °C for 24 hours (in an ultralow-temperature freezer), and then the sample was lyophilized in a 2.5-L LABCONCO freeze-dryer at a pressure of 0.018 mbar and −54 °C. Finally, three residues were obtained for each propolis sample: chloroform residue (RCHCl3), butanolic residue (RBuOH), and aqueous residue (RH2O) (Simões et al., 2004; Yang et al., 2011).\n\nAfter the propolis partitions were obtained, RCHCl3 was fractionated using Sephadex LH-20 as the stationary phase and the solvents petroleum ether (PE), dichloromethane (DCM), and methanol (MeOH) as the mobile phase. RCHCl3 propolis was first solubilized with PE. Open-column chromatography was performed with Sephadex LH-20 as the stationary phase (100 g) in PE. The solubilized sample was added to the column and eluted with PE (450 mL), followed by DCM (350 mL), and finally with MeOH (500 mL), thus yielding the PE fraction, dichloromethane fraction, and methanolic fraction. The fractions obtained were dried in an extraction hood for 24 hours (Mancarz et al., 2019; Yang et al., 2011).\n\nFinally, the three dry fractions were transferred to the Bacteriology Laboratory of the Universidad Peruana Cayetano Heredia for antimicrobial sensitivity tests.\n\nS. gordonii strains (ATCC® 51656™) and F. nucleatum (ATCC® 10953™) were used for the antibacterial susceptibility and antibiofilm assays. The microorganisms were imported directly from the American Type Culture Collection (ATCC, USA) and cultured in the Bacteriology Laboratory of the Research and Development laboratories, School of Sciences and Philosophy of the Universidad Peruana Cayetano Heredia (Voos et al., 2014).\n\nThe disk diffusion method was used for the antimicrobial susceptibility test. Petri dishes containing trypticase soy agar (TSA) were prepared for S. gordonii (ATCC® 51656™). Petri dishes containing TSA supplemented with 5% sheep blood, hemin (5 mg/L), and menadione (1 mg/L) were prepared for F. nucleatum (ATCC® 10953™). The dishes were monitored for 24 hours to confirm their sterility (Millones-Gómez et al., 2020).\n\nThe challenge was performed by embedding a swab with the previously prepared inoculum, spreading the inoculum on the surface of the agar four times, allowing it to stand for five minutes, and then placing Whatman No. 3 filter paper discs (6-mm diameter) impregnated with 10 μL of each of the propolis extracts 25 mg/mL on top but away from one another. This procedure was repeated four times to yield plates for each of the extracts (CE, partitions, and fractions). A 0.12% chlorhexidine solution was used as a positive control, and dimethyl sulfoxide (DMSO) and Milli-Q water (1:1) were used as negative controls. The evaluation of antibacterial activity was carried out by means of inhibition zones in millimeters using a Truper calibrator (Millones-Gómez et al., 2020).\n\nAfter evaluating the CEs of the 13 propolis samples, we decided that partitions would only be performed on the extracts that exhibited zones of inhibition on both strains studied, and then we could perform cytotoxic evaluations against human gingival fibroblasts.\n\nCytotoxicity was evaluated in the dentistry laboratory of the Center for Research and Development in Health Sciences of the Universidad Autónoma de Nuevo León, Mexico. The cytotoxic effect of propolis on human gingival fibroblast cell line (HGF-1 ATCC® CRL-2014, American Type Culture Collection; USA) was determined by adapting the cell viability method for microplates using the MTT assay as described below (Devequi-Nunes et al., 2018; Poggio et al., 2017). Cytotoxicity responses were classified as severe (30%), moderate (30-60%), mild (60-90%), or noncytotoxic (> 90%) (Poggio et al., 2017).\n\nAfter evaluating cytotoxicity, we decided that only residues that showed cell viability greater than 90% in the HGF-1 cell line (ATCC® CRL-2014) would be fractionated and evaluated for antimicrobial activity.\n\nThe method used was microdilution in broth using 96-well microtiter plates. Chlorhexidine at 0.12% was the positive control, and diluted DMSO solution with Milli-Q water (1:1) was the negative control. The entire procedure was repeated four times for each propolis sample with the largest inhibition zones (Millones-Gómez et al., 2020). The minimum inhibitory concentration of propolis was deemed to be the concentration in the well where no development was observed (turbidity) using a spectrophotometer.\n\nAfter determining the minimum inhibitory concentration of fractions with zones of inhibition on both strains studied, we evaluated the biofilm considering those concentrations with antibacterial and nontoxic effects on the HGF-1 cell line (ATCC® CRL-2014).\n\nEach strain was inoculated from a colony into 15 mL of Trypticase soy broth and incubated at 37 °C in anaerobiosis until reaching the exponential growth phase of S. gordonii (four hours and 30 minutes) and F. nucleatum (eight hours), which was shown by an optical density of 550 nm and 0.125 nm with 150 × 106 cells/mL (Sánchez et al., 2011).\n\nSubsequently, the surfaces of Thermo Scientific Nunc Lab-Tek Chamber Slides were prepared with 30 μL of poly-l-lysine incubated at RT for 30 minutes and then allowed to dry at 37 °C for 24 hours under sterile conditions. Then, 300 μL of artificial saliva was added for incubation at 4 °C for 16 hours. The sheets were washed with 300 μl of phosphate-buffered saline (PBS 1×) twice. A total of 280 μL of brain heart infusion (BHI) + 2.5% sucrose was added. Finally, 10 μL of S. gordonii + 10 μL of F. nucleatum was inoculated, and then each slide was incubated for 24 hours at 37 °C under anaerobic conditions (Sánchez et al., 2011).\n\nBiofilm analysis by polymerase chain reaction (PCR) was performed in the Bioinformatics and Molecular Biology Laboratory of the Research and Development Laboratories of Universidad Peruana Cayetano Heredia. To confirm the presence of both species, DNA was extracted from the cultured biofilms at 48 and 120 hours. The DNA concentration was quantified in a Thermo Scientific Nanodrop 2000 using Maxima SYBR Green/ROX qPCR Master Mix (2X) (for absolute quantification by real-time PCR using the following cycling conditions: Initial denaturation: 95 °C, 3 min. PCR cycling 45 cycles (95 °C, 15 s, 60 °C, 30 s). Each sample was diluted to 100 ng/μL to determine the proportions of cells of both species (Sánchez, 2018; Sánchez et al., 2011).\n\nS. gordonii (Ayala et al., 2016; Cayo et al., 2016) and F. nucleatum (Jacinto, 2018; Sánchez, 2018) were identified using specific primers:\n\nsrtA F 5′ TATTATGGTGCTGGTACGATGAAAGAGACTC 3′;\n\nsrtA R 5′ TATAGATTTTCATACCAGCCTTAGCACGATC 3′;\n\nradD F 5′ GGATTTATCTTTGCTAATTGGGGAAATTATAG 3′; and\n\nradD R 5′ ACTATTCCATATTCTCCATAATATTTCCCATTAGA 3′.\n\nTo evaluate the effect of propolis on the biofilm, 10 μL of S. gordonii + 10 μL of F. nucleatum was inoculated, and then each plate was incubated for 24 hours at 37 °C under anaerobic conditions. The propolis fraction with the greatest antibacterial effect and lowest toxicity against HGF-1 cells was used.\n\nThe first dose of the propolis extract was administered 24 hours after its formation, where the supernatant was carefully removed from each well. Two washes were performed without exerting much force with 300 μL of PBS (1×). Then, 300 μL of propolis was added, followed by incubation for 1 minute at RT. The plate was removed and washed up to the surface of each well with 300 μL of PBS (1×) twice. Next, 300 μL of sterile BHI + SAC 2.5% culture medium was added, and the plate was incubated at 37 °C for 24 hours under anaerobic conditions (Sánchez et al., 2011).\n\nThe following groups were formed:\n\n- Group 1 (Sg + Fn): 300 μL of propolis was pipetted in each well every 24 hours until evaluation at two days and five days.\n\n- Group 2 (negative control): 300 μL DMSO + Milli-Q water (1:1) was pipetted in each well every 24 hours until evaluation at two days and five days.\n\n- Group 3 (positive control): 300 μL of 0.12% chlorhexidine was pipetted in each well every 24 hours until evaluation at two days and five days.\n\n- Three repetitions of each group were performed.\n\nThe final exposure of the slide occurred when the biofilms reached 120 hours of maturation, where the Nunc Lab-Tek Chamber Slide™ system fixation and staining procedure was performed with fluorochromes for confocal microscopy.\n\nThe removable chamber was taken off the surface of the Lab-Tek slide, placed horizontally to fix each surface of each well with 30 μL of 4% paraformaldehyde (4%) that was added over the entire surface of the biofilm, and incubated RT for 20 minutes. Then, three gentle washes were performed with 1× PBS. Five microlitres of the L13152 LIVE/DEAD® BacLight bacterial viability kit was added at a concentration ratio of 1:1 with fluorochromes to the surface of the biofilm. The cells were stained with 5 μL of VECTASHIELD® HardSet™ Antifade Mounting Medium with DAPI (4′,6-diamidino-2-phenylindole).\n\nH-1500-10.This last step was performed to differentiate the nucleic acids (DNA) in the bacteria and conserve the samples (Sánchez et al., 2011).\n\nBiofilm thickness was evaluated in the Microscope Core, Neuroscience Department, School of Medicine, University of California San Diego - USA using a Zeiss LSM880 confocal microscope. Biofilm thickness (vertical growth) was measured with an LSM880 confocal microscope (Zeiss) using the Z-Stacks option (3D images). The images were captured with the Zeiss Plan-Apochromat objective of 63×/1.4 oil objective, with two different zooms. The resulting images were processed using Zeiss Zen Black software (version 2012), and the results were read in micrometres (Figures 1A, 1B, 2A, 2B, and 3).\n\nImages taken by confocal microscopy (Zeiss LSM 880). A) Zoom 1. B) Zoom 4. DAPI, 4′,6-diamidino-2-phenylindole.\n\nA) Zoom 1. B) Zoom 3. DAPI, 4′,6-diamidino-2-phenylindole.\n\nImages taken by confocal microscopy (Zeiss LSM 880).\n\nThe major chemical components of the propolis fraction with effects on the biofilm were analysed through proton- and C-13 nuclear magnetic resonance (1H NMR and 13C NMR) at the Analytical Center of the Institute of Chemistry of the University of São Paulo, Brazil. A 25-mg sample was solubilized in MERCK brand deuterated methanol, and NMR spectra were recorded in a 500-MHz Bruker spectrometer operating at 500 MHz to obtain the hydrogen spectra and operating at 125 MHz for the C-13 spectra (Figures 4 and 5).\n\nThen, a 2-mg sample of FMeOH from RCHCl3 of Oxapampa propolis was solubilized in methanol (CH3OH), filtered through a filter with a pore size of 0.45 μm, and transferred to a 2-mL vial. The sample was analysed by liquid chromatography coupled to mass spectrometry (LC/MS) at the Laboratory of Natural Products of the Institute of Chemistry of the University of São Paulo, Brazil. The liquid chromatographer was of the Shimadzu brand (Kyoto, Japan), which consists of two LC-20AD model analytical pumps, with an SIL-20AHT automatic injector and an SPD-20A UV/Vis detector, an oven for the CTO-20A column, and a CBM-20A controller. The mobile phase consisted of two solvents: solvent A: 0.2% formic acid in water and solvent B: acetonitrile (ACN). The gradient used was 5% B T0-2 minutes, and for T2-35 minutes, a gradient up to 100% B, T35-45 minutes was maintained at 100% B. The column was a Luna 5u PFP (2) 100 A, 150 × 2 mm (Phenomenex). The analyses were performed at 254 nm and 280 nm, the oven for the column was set at 40 °C, and the flow of the mobile phase to the mass spectrometer was 200 μL/min (Figure 6).\n\nThe mass spectrometer (Bruker MicroTOF-QII) operated in positive MS/MS mode with N2 gas for nebulization and drying at 4 bar and 8 L/min, respectively. The drying temperature was programmed at 200 °C, the collision and quadrupole energies were 10 and 8 eV, respectively, and the capillary received a charge of 4,500 V. Cones RF1 and RF2 were programmed at 400 and 200 Vpp, respectively, and the hexapole RF and collision RF were both set at 200 Vpp. The mass reading range was 100 to 1,000 kDa (Narimane et al., 2020; Pobiega et al., 2019; Sun et al., 2015) (Figure 7).\n\nFor the analysis, the statistical software SPSS version 25.0 was used. The Kruskal-Wallis test was used to compare the average range of each treatment with the average range of all of them. The Z test was used to individually compare the average range of each type of treatment to the average range of all treatments. Dunn’s multiple comparisons test was used for decision processes in sequential experiments.\n\n\nResults\n\nThe objective of this study was to evaluate the antibacterial effect of the CEs of 13 propolis isolates from the Peruvian Andes (Table 2). The microscopy images and raw data are available in Underlying data (Millones-Gómez, 2021). The Kruskal-Wallis H test indicated a difference between some of the experimental and/or control propolis in their growth inhibition of both S. gordonii (p < 0.001) and F. nucleatum (p < 0.001). Likewise, the Z test revealed that, together with chlorhexidine (S. gordonii: 14.45 ± 0.30; F. nucleatum: 14.40 ± 0.18 mm), the propolis that exceeded the average inhibition in both types of bacteria were those from Oxapampa (10.88 ± 0.10 and 10.88 ± 0.10 mm), Chontabamba (10.0 ± 0.16 and 10.05 ± 0.19 mm), Saylla (10.00 ± 0.18 and 10.00 ± 0.14 mm), and Yura (9.98 ± 0.17 and 10.00 ± 0.16 mm). When performing post hoc comparisons of propolis with chlorhexidine, the difference in their average ranges was not statistically significant; thus, they are listed in Table 2 with the same letter.\n\n1 Kruskal-Wallis H, S. gordonii (p = 0.000 < 0.001) and F. nucleatum (p = 0.000 < 0.001), pairwise comparisons.\n\n2 Z-test for p-values (<0.05, <0.01, and <0.001): *,**, or *** indicates greater than the midrange, and +, ++, or +++ indicates less than the midrange; ns: not significant.\n\n3 Dunn test for multiple comparisons, where the same letter indicates no difference between treatments exceeding the average.\n\nWhen evaluating the CE partitions with the greatest antibacterial effect (Table 3), the Kruskal-Wallis H test indicated a difference between some of the experimental propolis partitions and/or controls in the growth inhibition of both S. gordonii (p < 0.001) and F. nucleatum (p < 0.001). Likewise, the Z test revealed that, together with chlorhexidine (S. gordonii: 14.45 ± 0.30 and F. nucleatum: 14.40 ± 0.18 mm), the partition that exceeded the average inhibition in both types of bacteria was the chloroform residue from Oxapampa (9.40 ± 0.28 and 9.95 ± 0.19 mm). The chloroform residues from Saylla (10.2 ± 0.14 mm) and Yura (9.27 ± 0.05 mm) showed above-average S. gordonii inhibition. The butanolic residues from Saylla (9.98 ± 0.21 mm) and Oxapampa (9.45 ± 0.19 mm) showed above-average inhibition of F. nucleatum. When performing post hoc comparisons of the best propolis with chlorhexidine, the difference in their average ranges was not statistically significant; thus, they are written in Table 3 with the same letter.\n\n1 Kruskal-Wallis H, S. gordonii (p = 0.000 < 0.001) and F. nucleatum (p = 0.000 < 0.001), pairwise comparisons.\n\n2 Z-test for p-values (<0.05, <0.01, and <0.001): *,**, or *** indicates greater than the midrange, and +, ++, or +++ indicates less than the midrange; ns: not significant.\n\n3 Dunn test for multiple comparisons, where the same letter indicates no difference between treatments exceeding the average.\n\nWhen evaluating the cytotoxicity of the propolis partitions on human gingival fibroblast cell line (HGF-1 ATCC® CRL-2014, American Type Culture Collection; USA) considering 10% Triton X-100 (negative control) and the medium (positive control) (Table 4), we generally observed that increasing the dilution decreased the cell viability of the partitions of the propolis evaluated. The chloroform partition of Oxapampa propolis showed its highest percentage of cell viability (92.64%) at the 0.78 mg/mL dilution.\n\nWhen evaluating the antibacterial effects of the fractions of the chloroform partition of Oxapampa propolis (Table 5) by the Kruskal-Wallis H test, a difference was identified in the inhibition of S. gordonii (p < 0.01) and F. nucleatum (p < 0.01) prepared in the different dilutions. The methanolic fraction of the chloroform residue of Oxapampa propolis (12.55 ± 0.19 and 12.15 ± 0.19 mm) had greater inhibition power against each bacterium than when combined with chlorhexidine (14.55 ± 0.19 and 14.33 ± 0.19 mm), exceeding the average. In addition, post hoc analysis revealed that both fractions did not differ from each other but had greater inhibitory power towards both bacteria.\n\n1 Kruskal-Wallis H, S. gordonii (p = 0.000 < 0.001) and F. nucleatum (p = 0.000 < 0.001), pairwise comparisons.\n\n2 Z-test for p-values (<0.05, <0.01, and <0.001): *,**, or *** indicates greater than the midrange, and +, ++, or +++ indicates less than the midrange; ns: not significant.\n\n3 Dunn test for multiple comparisons, where the same letter indicates no difference between treatments exceeding the average.\n\nWhen evaluating the concentrations of 0.781 and 1.563 mg/mL of the methanolic fraction of the chloroform residue of Oxapampa propolis on biofilm thickness by confocal microscopy, the Kruskal-Wallis H test indicated that there was a difference in the thickness of the biofilm formed with the different treatments, both at 48 hours (p < 0.01) and at 120 hours (p < 0.001). The biofilm formed with 0.12% chlorhexidine (8,100 ± 1,149 and 45,200 ± 5,718 μm) was not thinner than the average, as shown in Table 6, at either 48 hours or 120 hours (p > 0.05). The biofilms with lower-than-average thickness were those formed with 0.78 mg/μL propolis (8.026 ± 1.609 and 6.840 ± 1.675 μm) and 1.56 mg/μL propolis (7.374 ± 1.620 and 9.248 ± 0.679 μm). Post hoc tests indicated that these did not differ from chlorhexidine in the biofilm formed at 48 hours; but at 120 hours, although they did not differ from each other, propolis made with a concentration of 0.78 mg/μL was thinner than that made with chlorhexidine.\n\n1 Kruskal-Wallis H, S. gordonii (p = 0.000 < 0.001) and F. nucleatum (p = 0.000 < 0.001), pairwise comparisons.\n\n2 Z-test for p-values (<0.05, <0.01, and <0.001): *,**, or *** indicates greater than the midrange, and +, ++, or +++ indicates less than the midrange; ns: not significant.\n\n3 Dunn test for multiple comparisons, where the same letter indicates no difference between treatments exceeding the average.\n\nWhen evaluating the effect of the methanolic fraction of the chloroform residue of Oxapampa propolis on the number of bacteria by quantifying the number of copies of the srtA gene of S. gordonii and the radD gene of F. nucleatum in the biofilm by PCR, the Kruskal-Wallis H test indicated that there was a difference in the number of S. gordonii (p < 0.01, in both periods) and in the number of F. nucleatum (p < 0.05 in both periods) under the different treatments. The concentration of propolis of 1.56 mg/mL decreased the amount of S. gordonii both at 48 (6.347 ± 0.410) and at 120 hours (5.157 ± 0.202) and the amount of F. nucleatum at 120 hours (5.747 ± 0.618) compared to the average, as did 0.12% chlorhexidine. However, the post hoc analysis indicated that this concentration showed no difference from chlorhexidine in the control of the development of both bacteria in the times evaluated (Table 7).\n\n1 Kruskal-Wallis H, S. gordonii (p = 0.000 < 0.001) and F. nucleatum (p = 0.000 < 0.001), pairwise comparisons.\n\n2 Z-test for p-values (<0.05, <0.01, and <0.001): *,**, or *** indicates greater than the midrange, and +, ++, or +++ indicates less than the midrange; ns: not significant.\n\n3 Dunn test for multiple comparisons, where the same letter indicates no difference between treatments exceeding the average.\n\n\nDiscussion\n\nThe present study aimed to evaluate the antibacterial effect of CEs, partitions, and fractions of Peruvian propolis and the effects of fractions on the thickness of in vitro biofilms of S. gordonii and F. nucleatum. Of the 13 CEs of propolis evaluated, only four showed antibacterial effects on both strains. Moreover, the methanolic fraction of Oxapampa propolis showed an effect on the thickness of the biofilm created in vitro.\n\nThe results of the present investigation showed that of the 13 Peruvian propolis isolates evaluated, four showed antibacterial effects on both bacterial strains. These results differ from those of other investigations that have shown the strong antibacterial power of propolis against all evaluated microorganisms (Becerra et al., 2019; Bueno-Silva et al., 2013; Dantas Silva et al., 2017; Trusheva et al., 2004). Although several studies of Peruvian propolis have shown effects on oral bacteria, all of them focused on other types of oral bacteria. Examples include the La Libertad propolis against Streptococcus mutans (Becerra et al., 2019; Sánchez, 2018); Huacho and Cajabamba propolis against Streptococcus mutans (Ayala et al., 2016; Cayo et al., 2016); and propolis from Arequipa, Huánuco, and Huaraz against Streptococcus mutans and Streptococcus oralis (Jacinto, 2018; Vargas, 2019). This study is the first to evaluate the effects of Peruvian propolis on bacteria linked to the growth of subgingival biofilms.\n\nThe CEs of propolis with the largest zones of inhibition were those from apiaries in Chontabamba, Saylla, Yura, and Oxapampa, with the last being widely studied and showing similar effects in previous studies (Alemán et al., 2018; Eguizábal & Nakata, 2014; Tovalino & Contreras, 2010). The boundless vegetation of the Oxapampa valley, where species such as Dictyocaryum lamarckianum (palm tree), Juglans neotropica (Andean walnut), Cyrtocymura scorpioides, Vernonanthura patens (Kunth), Baccharis latifolia, Cecropia spp., Inga spp., and Pinus tecunumanii (timber tree), combined with the tropical climate of this area (Muñoz & Del Pilar, 2015), offer a variety of active components that are transported by bees to their hives in the form of propolis (Fernández-Calderón et al., 2020; Okińczyc et al., 2020; Rivera & Mesía, 2009). This variety enhances their biological properties.\n\nIn the present study, after identifying the CEs of the four propolis with the greatest zones of inhibition on each bacterium evaluated, partitions were performed, and the strongest antibacterial effects were found in the butanolic and chloroform residues of all the propolis studied. Although there are no studies with partitions of Peruvian propolis, the few studies carried out on propolis from other sources indicate that some solvents have greater affinity for certain components with biological effects (Flemming et al., 2016). For example, the amounts of flavonoids and terpenes in different extracts were found to decrease in the following order: chloroform extract > ethanolic extract > butanolic extract (Osés et al., 2020; Palomino et al., 2009).\n\nIn Peru, as in many countries, beekeepers prepare by hand the products derived from the hive. Many therapeutic effects have been attributed to propolis (Narimane et al., 2020). However, many of these products could be used without any control, with several of them being toxic for human consumption; therefore, the toxicity must be correctly recognized and the product used reasonably (Sun et al., 2015). In the present study, toxicity to gingival fibroblasts was evaluated by the percentage of cell viability (Poggio et al., 2017). Only the chloroform residue of Oxapampa propolis was found to be nontoxic; the results of the MTT assay, with more than 92% cell viability, suggest good biocompatibility. Although few studies have evaluated the cytotoxicity of propolis on this cell line, they show that these are not very toxic (Pobiega et al., 2019; Santos et al., 2019).\n\nWhen evaluating the fractions of the chloroform partition, only the methanolic fraction had an inhibitory effect, with a minimum inhibitory concentration of 0.78 mg/mL on both strains evaluated. Although no studies of Peruvian propolis have been reported, studies of foreign propolis have found similar results (Nani et al., 2018; Zeng & Jiang, 2010), demonstrating that methanolic extraction can produce a higher concentration of compounds with biological activity (Flemming et al., 2016).\n\nMost bacteria reside naturally in accumulations called biofilms, which are substantially more tolerant to antimicrobials than free-floating cells (Aydin et al., 2018). A biofilm is a community of bacteria that have adhered to a surface. Once adhered, the cells begin to secrete extracellular polymeric substances composed of extracellular DNA, polysaccharides, and proteins. These extracellular substances trap nutrients and water within the biofilm, allowing cells to mature in nutrient-rich conditions while protecting them from desiccation, host immune defences, and antimicrobial agents (Cabral et al., 2009). In the present study, when evaluating the effect of the methanolic fraction of propolis on biofilm thickness, both concentrations were found to have a greater effect than chlorhexidine at 120 hours. This result may have occurred because one of the factors contributing to the resistance of biofilm-mediated infections may be a delay in the penetration of loaded antimicrobial agents due to the binding of the robust extracellular polymeric substance matrix, which prevents complete access to the entire biofilm (Das Neves et al., 2016; Li et al., 2016). However, unlike chlorhexidine, the propolis fraction is composed of more than one active component, including flavonoids, phenolic acids, terpenes, aromatic acids, and others (Sha et al., 2009). Identifying the exact chemical substances underlying a certain effect, as well as their defined biochemical mechanisms, is difficult (Hall & Mah, 2017; Khatoon et al., 2018).\n\nThe PCR results showed that the concentration of 1,563 mg/mL of the methanolic fraction of propolis decreased the copy numbers of the srtA gene of S. gordonii and the radD gene of F. nucleatum at 120 hours. Although no previous studies have evaluated the effect of propolis on biofilms of these species, some research suggests that propolis has a dose-dependent effect on the inhibition of genes involved in adherence, showing a potential effect beyond bacterial growth inhibition (Veloz et al., 2019a, 2019b).\n\nThe results of component identification by LC/MS of the methanolic fraction of Oxapampa propolis showed the presence of rhamnocitrin, apigenin, kaempferol, isorhamnetin, diosmetin, acacetin, glycitein, and chrysoeriol. The first three compounds have already been described to have antibiofilm effects in previous studies (Palomino et al., 2009). Previous studies have highlighted apigenin as a flavonoid with considerable antibiofilm potency (Nani et al., 2018; Palomino et al., 2009) due to its ability to increase the permeability of the bacterial membrane, resulting in cellular apoptosis (Zeng et al., 2010). Other studies have highlighted the potential of flavonoids to inhibit the formation of the extracellular polymeric matrix, exposing cells that form biofilms and increasing their susceptibility to antimicrobial therapies (Aydin et al., 2018).\n\nThe results of this study show a significant antibiofilm effect of Oxapampa propolis without causing damage to oral human cells (gingival fibroblasts), rendering it a promising option for evaluation as a new molecule for the development of new pharmacological agents that may be valuable in the dentistry field.\n\n\nData availability\n\nMendeley Data: Databases (antibiofilm assays). https://doi.org/10.17632/3bc8dd6x3t.3 (Millones-Gómez, 2021).\n\nThis project contains the following underlying data:\n\n- Raw microscopy images\n\n- CT data.xlsx\n\n- Raw data.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAbbasi AJ, Mohammadi F, Bayat M: Applications of propolis in dentistry: A review. Ethiop. J. Health Sci. 2018; 28(4): 505–512. Publisher Full Text\n\nAlemán RMH, Ramírez CMG, Carhuapoma-Yance M, et al.: Efecto inhibidor in vitro del extracto etanólico de propóleo al 15% y 30% frente a cepas de Lactobacillus acidophilus. Revista Estomatológica Herediana. 2018; 28(1): 36–43. Publisher Full Text\n\nAlencar SM, Oldoni TLC, Castro ML, et al.: Chemical composition and biological activity of a new type of Brazilian propolis: Red propolis. J. Ethnopharmacol. 2007; 113(2): 278–283. PubMed Abstract | Publisher Full Text\n\nAlmuhayawi MS: Propolis as a novel antibacterial agent. Saudi Journal of Biological Sciences. 2020; 27(11): 3079–3086. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAndersen ME, McMullen PD, Phillips MB, et al.: Developing context appropriate toxicity testing approaches using new alternative methods (NAMs). ALTEX. 2019; 36(4): 532–534. Publisher Full Text\n\nArbia L, Chikhi-Chorfi N, Betatache I, et al.: Antimicrobial activity of aqueous extracts from four plants on bacterial isolates from periodontitis patients. Environ. Sci. Pollut. Res. 2017; 24(15): 13394–13404. PubMed Abstract | Publisher Full Text\n\nAsawahame C, Sutjarittangtham K, Eitssayeam S, et al.: Antibacterial activity and inhibition of adherence of Streptococcus mutans by propolis electrospun fibers. AAPS PharmSciTech. 2015; 16(1): 182–191. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAyala CI, Castillo EF, Graus L: Propóleo peruano en el desarrollo de un enjuague bucal con actividad antibacteriana. Arnaldoa. 2016; 23(1): 171–184.\n\nAydin ZU, Akpinar KE, Hepokur C, et al.: Assessment of toxicity and oxidative DNA damage of sodium hypochlorite, chitosan and propolis on fibroblast cells. Braz. Oral Res. 2018; 32: e119. Publisher Full Text\n\nBarbosa Bezerra GB, De Souza LD, Dos Santos AS, et al.: Hydroalcoholic extract of Brazilian red propolis exerts protective effects on acetic acid-induced ulcerative colitis in a rodent model. Biomed. Pharmacother. 2017; 85: 687–696. PubMed Abstract | Publisher Full Text\n\nBecerra TB, Calla-Poma RD, Requena-Mendizabal MF, et al.: Antibacterial effect of peruvian propolis collected during different seasons on the growth of Streptococcus mutans. Open Dent. J. 2019; 13(1): 327–331. Publisher Full Text\n\nBentz J, O'Connor MP, Bednarczyk D, et al.: Variability in P-glycoprotein inhibitory potency (IC50) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab. Dispos. 2013; 41(7): 1347–1366. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBonamigo T, Campos JF, Alfredo TM, et al.: Antioxidant, cytotoxic, and toxic activities of propolis from two native bees in Brazil: Scaptotrigona depilis and Melipona quadrifasciata anthidioides. Oxidative Med. Cell. Longev. 2017; 2017: 1–12. Publisher Full Text\n\nBryan J, Redden P, Traba C: The mechanism of action of Russian propolis ethanol extracts against two antibiotic-resistant biofilm-forming bacteria. Lett. Appl. Microbiol. 2016; 62(2): 192–198. PubMed Abstract | Publisher Full Text\n\nBueno-Silva B, Alencar SM, Koo H, et al.: Anti-inflammatory and antimicrobial evaluation of neovestitol and vestitol isolated from Brazilian red propolis. J. Agric. Food Chem. 2013; 61(19): 4546–4550. PubMed Abstract | Publisher Full Text\n\nBueno-Silva B, Kawamoto D, Ando-Suguimoto ES, et al.: Brazilian red propolis attenuates inflammatory signaling cascade in LPS-activated macrophages. PLoS One. 2015; 10(12): e0144954. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBueno-Silva B, Kawamoto D, Ando-Suguimoto ES, et al.: Brazilian red propolis effects on peritoneal macrophage activity: Nitric oxide, cell viability, pro-inflammatory cytokines and gene expression. J. Ethnopharmacol. 2017; 207: 100–107. PubMed Abstract | Publisher Full Text\n\nBueno-Silva B, Marsola A, Ikegaki M, et al.: The effect of seasons on Brazilian red propolis and its botanical source: Chemical composition and antibacterial activity. Nat. Prod. Res. 2016; 31(11): 1318–1324. PubMed Abstract | Publisher Full Text\n\nCabral ISR, Oldoni TLC, Prado A, et al.: Composição fenólica, atividade antibacteriana e antioxidante da própolis vermelha Brasileira. Química Nova. 2009; 32(6): 1523–1527. Publisher Full Text\n\nCardoso JG, Iorio NLP, Rodrigues LF, et al.: Influence of a Brazilian wild green propolis on the enamel mineral loss and Streptococcus mutans’ count in dental biofilm. Arch. Oral Biol. 2016; 65: 77–81. PubMed Abstract | Publisher Full Text\n\nCayo C, Quijandría L, Ramos J: In vitro evaluation of the antibacterial effect of Propolis on cultures of Streptococcus mutans (ATCC 25175). Ciencia y Desarrollo. 2016; 19(2): 19–24. Publisher Full Text\n\nChen YW, Ye SR, Ting C, et al.: Antibacterial activity of propolins from Taiwanese green propolis. J. Food Drug Anal. 2018; 26(2): 761–768. PubMed Abstract | Publisher Full Text\n\nChoi JU, Lee JB, Kim KH, et al.: Comparison of periodontopathic bacterial profiles of different periodontal disease severity using multiplex real-time polymerase chain reaction. Diagnostics (Basel, Switzerland). 2020; 10(11): 965. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDantas Silva RP, Machado BAS, Barreto GDA, et al.: Antioxidant, antimicrobial, antiparasitic, and cytotoxic properties of various Brazilian propolis extracts. PLoS One. 2017; 12(3): e0172585. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDas Neves MVM, Da Silva TMS, Lima EDO, et al.: Isoflavone formononetin from red propolis acts as a fungicide against Candida sp. Braz. J. Microbiol. 2016; 47(1): 159–166. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDe Francisco LMB, Pinto D, Rosseto HC, et al.: Design and characterization of an organogel system containing ascorbic acid microparticles produced with propolis by-product. Pharm. Dev. Technol. 2019; 25(1): 54–67. PubMed Abstract | Publisher Full Text\n\nDe Freitas MCD, De Miranda MB, De Oliveira DT, et al.: Biological activities of red propolis: A review. Recent Patents on Endocrine, Metabolic and Immune Drug Discovery. 2018; 11(1): 3–12. Publisher Full Text\n\nDevequi-Nunes D, Machado BAS, Barreto GDA, et al.: Chemical characterization and biological activity of six different extracts of propolis through conventional methods and supercritical extraction. PLoS One. 2018; 13(12): e0207676. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEguizábal M, Nakata HM: Actividad antibacteriana in vitro del extracto etanólico de propóleo peruano sobre Streptococcus mutans y Lactobacillus casei. Odontol Sanmarquina. 2014; 10(2): 18–20. Publisher Full Text\n\nEl-Guendouz S, Aazza S, Lyoussi B, et al.: Moroccan propolis: A natural antioxidant, antibacterial, and antibiofilm against Staphylococcus aureus with no induction of resistance after continuous exposure. Evid. Based Complement. Alternat. Med. 2018; 2018: 1–19. Publisher Full Text\n\nEldeniz AU, Mustafa K, Ørstavik D, et al.: Cytotoxicity of new resin-, calcium hydroxide- and silicone-based root canal sealers on fibroblasts derived from human gingiva and L929 cell lines. Int. Endod. J. 2007; 40(5): 329–337. PubMed Abstract | Publisher Full Text\n\nFernández-Calderón MC, Navarro-Pérez ML, Blanco-Roca MT, et al.: Chemical profile and antibacterial activity of a novel Spanish propolis with new polyphenols also found in olive oil and high amounts of flavonoids. Molecules. 2020; 25(15): E3318. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFlemming HC, Wingender J, Szewzyk U, Steinberg P, et al.: Biofilms: An emergent form of bacterial life. Nat. Rev. Microbiol. 2016; 14(9): 563–575. PubMed Abstract | Publisher Full Text\n\nFreires IA, De Alencar SM, Rosalen PL: A pharmacological perspective on the use of Brazilian red propolis and its isolated compounds against hμman diseases. Eur. J. Med. Chem. 2016; 110: 267–279. PubMed Abstract | Publisher Full Text\n\nGeng H, Yuan Y, Adayi A, et al.: Engineered chimeric peptides with antimicrobial and titanium-binding functions to inhibit biofilm formation on Ti implants. Mater. Sci. Eng. C. 2018; 82: 141–154. PubMed Abstract | Publisher Full Text\n\nHall CW, Mah TF: Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol. Rev. 2017;41(3): 276–301. PubMed Abstract | Publisher Full Text\n\nHochheim S, Pacassa Borges P, Boeder AM, et al.: A bioguided approach for the screening of antibacterial compounds isolated from the hydroalcoholic extract of the native Brazilian bee's propolis using mollicutes as a model. Front. Microbiol. 2020; 11: 558. Publisher Full Text\n\nJacinto DD: Efecto antibacteriano entre tres concentraciones de extracto etanólico de propóleo de Cajabamba y un propóleo comercial, sobre cepas de Streptococcus mutans ATCC 25175. Universidad Católica Los Ángeles de Chimbote;2018. [Tesis Pregrado].\n\nKhatoon Z, McTiernan CD, Suuronen EJ, et al.: Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention. Heliyon. 2018; 4(12): e01067. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKouidhi B, Al Qurashi YMA, Chaieb K: Drug resistance of bacterial dental biofilm and the potential use of natural compounds as alternative for prevention and treatment. Microb. Pathog. 2015; 80: 39–49. PubMed Abstract | Publisher Full Text\n\nLazar V, Saviuc CM, Carmen Chifiriuc M: Periodontitis and periodontal disease - innovative strategies for reversing the chronic infectious and inflammatory condition by natural products. Curr. Pharm. Des. 2015; 22(2): 230–237. Publisher Full Text\n\nLee J, Nho YH, Yun SK, et al.: Use of ethanol extracts of Terminalia chebula to prevent periodontal disease induced by dental plaque bacteria. BMC Complement. Altern. Med. 2017; 17(1): 113. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi A, Xuan H, Sun A, et al.: Preparative separation of polyphenols from water-soluble fraction of Chinese propolis using macroporous absorptive resin coupled with preparative high performance liquid chromatography. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2016; 1012-1013: 42–49. Publisher Full Text\n\nLotti C, Campo Fernandez M, Piccinelli AL, et al.:2010; Chemical constituents of red Mexican propolis. J. Agric. Food Chem. 58(4): 2209–2213. PubMed Abstract | Publisher Full Text\n\nLupatini NR, Danopoulos P, Swikidisa R, et al.: Evaluation of the antibacterial activity of green propolis extract and meadowsweet extract against Staphylococcus aureus bacteria: Importance in would care compounding preparations. International Journal of Pharmaceutical Compounding. 2016; 20(4): 333–337. PubMed Abstract\n\nMancarz GFF, Laba LC, Da Silva ECP, et al.: Liquidambar styraciflua L.: A new potential source for therapeutic uses. J. Pharm. Biomed. Anal. 2019; 174: 422–431. PubMed Abstract | Publisher Full Text\n\nMarkiewicz-Żukowska R, Car H, Naliwajko SK, et al.: Ethanolic extract of propolis, chrysin, CAPE inhibit human astroglia cells. Adv. Med. Sci. 2012; 57(2): 208–216. PubMed Abstract | Publisher Full Text\n\nMartins ML, Leite KLDF, Pacheco-Filho EF, et al.: Efficacy of red propolis hydro-alcoholic extract in controlling Streptococcus mutans biofilm build-up and dental enamel demineralization. Arch. Oral Biol. 2018; 93: 56–65. PubMed Abstract | Publisher Full Text\n\nMartins ML, Monteiro ASN, Guimarães JEC, et al.: Cytotoxic and antibacterial effect of a red propolis mouthwash, with or without fluoride, on the growth of a cariogenic biofilm. Arch. Oral Biol. 2019; 107: 104512. PubMed Abstract | Publisher Full Text\n\nMillones-Gómez PA, Maurtua-Torres D, Bacilio-Amaranto R: Antimicrobial activity and antiadherent effect of Peruvian psidium guajava (Guava) leaves on a cariogenic biofilm model. J. Contemp. Dent. Pract. 2020; 21(7): 733–740. Publisher Full Text\n\nMillones-Gómez PA: Databases (antibiofilm assays). Mendeley Data. 2021; V3. Publisher Full Text\n\nMuñoz J, Del Pilar R: Evaluación in vitro del efecto inhibitorio de la terapia fotodinámica sobre Streptococcus mutans (ATCC® 25175) y Streptococcus sanguinis (ATCC® 10556) en presencia y ausencia de riboflavina. Universidad Peruana de Ciencias Aplicadas;2015. [Tesis Pregrado]\n\nNani BD, Franchin M, Lazarini JG, et al.: Isoflavonoids from Brazilian red propolis down-regulate the expression of cancer-related target proteins: A pharmacogenomic analysis. Phytother. Res. 2018; 32(4): 750–754. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNarimane S, Demircan E, Salah A, et al.: Correlation between antioxidant activity and phenolic acids profile and content of Algerian propolis: Influence of solvent. Pak. J. Pharm. Sci. 2020; 24(4 Suppl): 1679–1687. PubMed Abstract | Publisher Full Text\n\nOkińczyc P, Paluch E, Franiczek R, et al.: Antimicrobial activity of Apis mellifera L. and Trigona sp. propolis from Nepal and its phytochemical analysis. Biomed. Pharmacother. 2020; 129: 110435. PubMed Abstract | Publisher Full Text\n\nOryan A, Alemzadeh E, Moshiri A: Potential role of propolis in wound healing: Biological properties and therapeutic activities. Biomed. Pharmacother. 2018; 98: 469–483. PubMed Abstract | Publisher Full Text\n\nOsés SM, Marcos P, Azofra P, et al.: Phenolic profile, antioxidant capacities and enzymatic inhibitory activities of propolis from different geographical areas: Needs for analytical harmonization. Antioxidants (Basel, Switzerland). 2020; 9(1): 75. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPalomino L, García C, Gil J, et al.: Determinación del contenido de fenoles y evaluación de la actividad antioxidante de propóleos recolectados en el departamento de Antioquia (Colombia). Vitae. 2009; 16(3): 388–395.\n\nPasupuleti VR, Sammugam L, Ramesh N, et al.: Honey, propolis, and royal jelly: A comprehensive review of their biological actions and health benefits. Oxidative Med. Cell. Longev. 2017; 2017: 1–21. Publisher Full Text\n\nPiccinelli AL, Lotti C, Campone L, et al.: Cuban and Brazilian red propolis: Botanical origin and comparative analysis by high-performance liquid chromatography–photodiode array detection/electrospray ionization tandem mass spectrometry. J. Agric. Food Chem. 2011; 59(12): 6484–6491. PubMed Abstract | Publisher Full Text\n\nPobiega K, Kraśniewska K, Derewiaka D, et al.: Comparison of the antimicrobial activity of propolis extracts obtained by means of various extraction methods. J. Food Sci. Technol. 2019; 56(12): 5386–5395. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPoggio C, Riva P, Chiesa M, et al.: Comparative cytotoxicity evaluation of eight root canal sealers. J Clin Exp Dent. 2017; 9(4): e574–e578. Publisher Full Text\n\nPopova M, Lyoussi B, Aazza S, et al.: Antioxidant and α-glucosidase inhibitory properties and chemical profiles of Moroccan propolis. Nat. Prod. Commun. 2015; 10(11): 1934578X1501001. Publisher Full Text\n\nPrzybyłek I, Karpiński TM: Antibacterial properties of propolis. Molecules (Basel, Switzerland). 2019; 24(11): 2047. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRams TE, Degener JE, Van Winkelhoff AJ: Antibiotic resistance in human chronic periodontitis microbiota. J. Periodontol. 2014; 85(1): 160–169. PubMed Abstract | Publisher Full Text\n\nRivera RS, Mesía LH: Determinación de la flora polinífera del valle de Oxapampa (Pasco-Perú) en base a estudios palinológicos. Ecología Aplicada. 2009; 8(1-2): 53–59. Publisher Full Text\n\nSánchez JP: Comparación de la marcha fitoquímica de tres propóleos peruanos, y su efecto antibacteriano frente a cepas de Streptococcus mutans ATCC 25175. Universidad Católica Los Ángeles de Chimbote;2018. [Tesis Pregrado].\n\nSánchez MC, Llama-Palacios A, Blanc V, et al.: Structure, viability and bacterial kinetics of an in vitro biofilm model using six bacteria from the subgingival microbiota. J. Periodontal Res. 2011; 46(2): 252–260. PubMed Abstract | Publisher Full Text\n\nSantos FA, Bastos EMA, Uzeda M, et al.: Antibacterial activity of Brazilian propolis and fractions against oral anaerobic bacteria. J. Ethnopharmacol. 2002; 80(1): 1–7. PubMed Abstract | Publisher Full Text\n\nSantos LM, Fonseca MS, Sokolonski AR, et al.: Propolis: Types, composition, biological activities, and veterinary product patent prospecting. J. Sci. Food Agric. 2019; 100(4): 1369–1382. PubMed Abstract | Publisher Full Text\n\nSha N, Huang HL, Zhang JQ, et al.: Simultaneous quantification of eight major bioactive phenolic compounds in Chinese propolis by high-performance liquid chromatography. Nat. Prod. Commun. 2009; 4(6): 1934578X0900400–1934578X0900818. Publisher Full Text\n\nSimões LMC, Gregório LE, Da Silva Filho AA, et al.: Effect of Brazilian green propolis on the production of reactive oxygen species by stimulated neutrophils. J. Ethnopharmacol. 2004; 94(1): 59–65. PubMed Abstract | Publisher Full Text\n\nSlobodníková L, Fialová S, Rendeková K, et al.: Antibiofilm activity of plant polyphenols. Molecules (Basel, Switzerland). 2016; 21(12): 1717. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSocransky SS, Haffajee AD, Dzink JL, et al.: Associations between microbial species in subgingival plaque samples. Oral Microbiol. Immunol. 1988; 3(1): 1–7. PubMed Abstract | Publisher Full Text\n\nSun C, Wu Z, Wang Z, et al.: Effect of ethanol/water solvents on phenolic profiles and antioxidant properties of Beijing propolis extracts. Evid. Based Complement. Alternat. Med. 2015; 2015: 1–9. Publisher Full Text\n\nSvečnjak L, Marijanović Z, Okińczyc P, et al.: Mediterranean propolis from the adriatic sea Islands as a source of natural antioxidants: Comprehensive chemical biodiversity determined by GC-MS, FTIR-ATR, UHPLC-DAD-QqTOF-MS, DPPH and FRAP assay. Antioxidants (Basel, Switzerland). 2020; 9(4): 337. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTouzani S, Embaslat W, Imtara H, et al.: In vitro evaluation of the potential use of propolis as a multitarget therapeutic product: Physicochemical properties, chemical composition, and immunomodulatory, antibacterial, and anticancer properties. Biomed. Res. Int. 2019; 2019: 1–11. Publisher Full Text\n\nTovalino FRM, Contreras SS: Evaluación in vitro del efecto antibacteriano del extracto etanólico de propóleo de Oxapampa - Perú sobre cultivos de Streptococcus mutans (ATCC 25175) y Staphylococcus aureus (ATCC 25923). Revista Estomatológica Herediana. 2010; 20(1): 19–24. Publisher Full Text\n\nTrusheva B, Popova M, Naydenski H, et al.: New polyisoprenylated benzophenones from Venezuelan propolis. Fitoterapia. 2004; 75(7-8): 683–689. PubMed Abstract | Publisher Full Text\n\nUtispan K, Chitkul B, Monthanapisut P, et al.: Propolis extracted from the stingless bee Trigona sirindhornae inhibited S. mutans activity in vitro. Oral Health and Preventive Dentistry. 2017; 15(3): 279–284. PubMed Abstract | Publisher Full Text\n\nVan Winkelhoff AJ, Herrera D, Oteo A, et al.: Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in the Netherlands and Spain. J. Clin. Periodontol. 2005; 32(8): 893–898. PubMed Abstract | Publisher Full Text\n\nVargas V: Evaluación de la marcha fitoquímica de tres propóleos peruanos, y su actividad antibacteriana frente a cepas de Streptococcus mutans (ATCC 25175) y Streptococcus oralis (ATCC 35037). Universidad Católica Los Ángeles de Chimbote;2019. [Tesis Pregrado].\n\nVeiga RS, De Mendonça S, Mendes PB, et al.: Artepillin C and phenolic compounds responsible for antimicrobial and antioxidant activity of green propolis and Baccharis dracunculifolia DC. J. Appl. Microbiol. 2017; 122(4): 911–920. PubMed Abstract | Publisher Full Text\n\nVeloz JJ, Alvear M, Salazar LA: Antimicrobial and antibiofilm activity against Streptococcus mutans of individual and mixtures of the main polyphenolic compounds found in Chilean propolis. Biomed. Res. Int. 2019a; 2019: 1–7. Publisher Full Text\n\nVeloz JJ, Alvear M, Salazar LA: Evaluation of alternative methods to assess the biological properties of propolis on metabolic activity and biofilm formation in Streptococcus mutans. Evid. Based Complement. Alternat. Med. 2019b; 2019: 1–8. Publisher Full Text\n\nVerma UP, Gupta A, Yadav RK, et al.: Cytotoxicity of chlorhexidine and neem extract on cultured human gingival fibroblasts through fluorescence-activated cell sorting analysis: An in-vitro study. Euro. J. Dentistry. 2018; 12(3): 344–349. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVoos AC, Kranz S, Tonndorf-Martini S, et al.: Photodynamic antimicrobial effect of safranine O on an ex vivo periodontal biofilm. Lasers Surg. Med. 2014; 46(3): 235–243. PubMed Abstract | Publisher Full Text\n\nYang H, Dong Y, Du H, et al.: Antioxidant compounds from propolis collected in Anhui, China. Molecules. 2011; 16(4): 3444–3455. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZabaiou N, Fouache A, Trousson A, et al.: Biological properties of propolis extracts: Something new from an ancient product. Chem. Phys. Lipids. 2017; 207: 214–222. PubMed Abstract | Publisher Full Text\n\nZeng ZP, Jiang JG: Analysis of the adverse reactions induced by natural product-derived drugs. Br. J. Pharmacol. 2010; 159(7): 1374–1391. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang CP, Shen XG, Chen JW, et al.: Artepillin C, is it a good marker for quality control of Brazilian green propolis?. Nat. Prod. Res. 2017; 31(20): 2441–2444. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "100736",
"date": "22 Nov 2021",
"name": "Luis Mariano Maita Castañeda",
"expertise": [
"Reviewer Expertise Studies on natural products"
],
"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 describes the bioactivity of Peruvian propolis extracts against specific bacteria and their ability to inhibit the growth of biofilms of S. goodonii and F. nucleatum. In particular, the authors selected, among the 13 samples, those with the highest bioactivity and evaluated the crude propolis extract, as well as the fractions, following a specific dissolution procedure.\nThe results are promising, in my opinion the work presents significant information on the quality of crude propolis and, in particular, on the composition of each fraction. As mentioned above, the composition of propolis depends to a large extent on the flora surrounding the apiaries, as well as on the climatic and geographical conditions that influence the flora.\n\nTranslated with www.DeepL.com/Translator (free version).\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": []
},
{
"id": "98525",
"date": "24 Nov 2021",
"name": "Myriam Angélica de la Garza-Ramos",
"expertise": [
"Reviewer Expertise Chemistry",
"microbiology and 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\nThe authors of the manuscript demonstrate the ability of Oxapampa propolis to inhibit the growth of two common oral pathogenic bacteria, with minimal effects on gingival fibroblasts at the minimum inhibitory concentration. In addition, the authors demonstrated the potential of Oxapampa propolis to inhibit biofilm formation using in vitro established biofilms of these same bacterial species. These aforementioned effects were found in the methanolic fractions of the chloroform residue of propolis extracts.\nAlthough further research is warranted on the safety and efficacy of oral therapies, as well as to better understand the bioactive compounds of these extracts (as indicated in the \"Discussion\" section), this work was logically and rigorously completed and offers valuable insight into a possible use of Oxapampa propolis as a cost-effective and readily available dental therapy presenting sufficient merit for 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?\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/10-1093
|
https://f1000research.com/articles/10-1311/v1
|
23 Dec 21
|
{
"type": "Research Article",
"title": "5G Millimeter-Wave Beamforming System using Substrate Integrated Waveguide",
"authors": [
"Noorlindawaty Md Jizat",
"Zubaida Yusoff",
"Arevinthran A/L Nallasamy",
"Yoshihide Yamada",
"Zubaida Yusoff",
"Arevinthran A/L Nallasamy",
"Yoshihide Yamada"
],
"abstract": "Beamforming is a key element of 5G that uses advanced antenna technologies to focus a wireless signal to a defined direction. Butler Matrix (BM) as a beamforming network is used to control the beam direction by utilizing the amplitude and the output phase. A particular technique for designing BM is through substrate integrated waveguide (SIW), which is used to realize the bilateral edge wall vias where the waveguide mode propagates through to support the current flow and reduce the loss of surface wave. Unlike conventional BM, the proposed design requires only hybrid couplers and phase shifter without any crossover. In this BM structure, the SIW hybrid coupler is designed, with two phase shifters of -90°, and one phase shifter of -180° to control the amplitude and phase shifting. This results in an optimized transmission amplitude and output phase difference. The BM also circumvents any crossover, to provide minimal losses. The hybrid coupler exhibits Sii and Sij characteristics at 28 GHz, with values of -27.35 dB for return loss, -3.9 dB for insertion loss, -3.2 dB for coupling, and -26.54 dB for the isolation. In the BM design, high transmission efficiency is observed where the return loss is less than -10 dB, while minimal transmission amplitudes are obtained within the values of ‒6 ± 3 dB. The three-port BM is designed using SIW with minimal loss and the phase difference at each respective output port of the BM shows values of 0°, -120°, and 120°. The three consecutive beams with the gains of 11.1 dBi for port 1 excitation, 9.06 dBi for port 2 excitation and 10.4 dBi for port 3 excitation is achieved when the antenna array is fed to the BM, and each of the radiated beams has beam angles of 0, -27 and 27 degrees.",
"keywords": [
"Millimeter-wave",
"substrate integrated waveguide",
"Butler Matrix",
"Three-ports",
"5G",
"antenna array",
"radiation pattern"
],
"content": "Introduction\n\nAn antenna with tracking capability is required in various applications, including 5G wireless communication in millimeter wave. However, in millimeter wave, high path loss arises, which increases quadratically with the frequency, ∝ f2, as defined by Friis’ law.1 To overcome this issue, beamforming and multiple-input, multiple-output (MIMO) systems are reported to be the key components of 5G systems that are to be deployed in 2020 and years to come.2–4 Multibeam antenna arrays automatically identify the most effective data delivery, while reducing interference for nearby users. Multibeam antenna arrays with passive beamforming are practically chosen due to their small size, low cost, and high gain.5–7\n\nButler Matrix (BM) is a well-known and simple design used for forming multiple beams with a linear array, where it can form orthogonal beams, and has a high beam crossover level. In this regard, a BM circuit has been found to be effective in developing alternative beams in various beam antenna-array systems.8–11 Since BM allows beam tracking for the selected users while suppressing unwanted signal, it has been identified as a preferred solution for 5G communication networks.12–13\n\nHowever, due to the four hybrids, four phase shifters and two crossovers in the conventional BM, the transmission line adds undesired effects, such as insertion loss.14 Substrate integrated waveguide (SIW) technology has been widely utilized due to its simple feeding network and low insertion loss.15–17 The SIW can control the aperture width to ensure that the system is tightly coupled. A new generation of high frequency integrated circuits, the SIW, as a type of rectangular dielectric-filled waveguide produced in a planar substrate with arrays of metallic vias or slots to produce bilateral edge walls, is a good candidate for generating low sidelobe antenna arrays.\n\nIn this work, a low loss SIW hybrid coupler is to be designed by realizing bilateral edge walls which control the current flow. The BM is to be designed by connecting the hybrid coupler with two -90° phase shifters and one phase shifter of -180°, with the respective reference to get the accurate output phase shift. This matrix is advantageous as it circumvents the crossover design, which is commonly used in the conventional design. The diameter and the pitch of the SIW via-hole is to be carefully designed to control the coupling throughout the BM path, to get a promising return loss and minimum transmission amplitude. The structure should be compact and low loss, which makes the BM suitable to be used in the beamforming application for the millimeter wave at 28 GHz.\n\n\nMethods\n\nIn this design, the substrate of Rogers R04350B, with a thickness of 0.254 mm, dielectric constant of 3.66 and loss tangent, (tan δ) of 0.0037, is chosen due to their excellent performance at higher frequencies. See underlying data18 for this section.\n\nAccording to Mohd Shukor et al.,19 a lower loss tangent is required in the substrate to ensure low dielectric loss and low dielectric absorption.\n\nQ-factor due to the dielectric, QD, is expressed in H. B. Jeon et al. (1) with a value of 302.56, where εeff, λ0 and αd are the effective dielectric constant, the wavelength in the air and the dielectric loss, respectively.\n\nIn the SIW configuration, an array of via holes is arranged in array configuration to create the mutual side walls and operate as a rectangular waveguide enabling the current to flow through it. Figure 1 shows the SIW structure, which has a via hole that is shorted in both planes to provide vertical current routes. Since these vertical metal fences are replaced by through via holes, the SIW propagation modes are comparable to those of rectangular waveguides.20–21 The SIW components in this segment have a via hole with a diameter of d and pitches of a and p, which represent the distance between the pairs of holes. With the optimized dimensions of the diameter and the pitches of the SIW into the coupler design, the proposed structure can fulfil the operational bandwidth at 28 GHz for millimetre wave.\n\nAs explained by Balanis,22 the resonance frequency was determined as shown in previous studies (2-4), where the width and length of the SIW cavity are appropriately optimized to accommodate the TE10 mode propagation. The SIW cavity's width and length are represented by weff and leff in the analysis:\n\nBased on (5-6), pitch should be kept short to reduce the leakage loss between nearby holes, where d is denoted as the diameter and p as the pitch (the distance between centre to centre of adjacent via holes).\n\nFigure 2 shows the signal path through three input and three output ports of the BM and Figure 3 (a), (b), and (c) illustrate the signal flow when the input is fed into In (I), In (II) and In (III), respectively. When the signal is fed into In (I), it passes through Coupler (II) and is divided into two outputs, where the first signal passes through Phase Shifter (I) producing an output signal of -180° at Out (I). The other signal passes Coupler (III) and Phase Shifter (III) producing an output signal of -180° at Out (II). The signal from Coupler (II) is coupled in Coupler (III) and produces an output of -180° at Out (III). The result obtained show the phase difference between these three output ports is 0°.\n\nWhen the signal is fed into In (II), the signal passes to each of the couplers and passes through the phase shifter according to the signal path. The first signal produces an output signal of -270° at Out (I). The signals to Out (II) produces an output signal of -90° and -360°. The superposition of the two signal vectors (-90°, -360°) formed at output port Out (II), results in an output signal value of -30°. Similarly, the signal from In (II) to the Out (III) passes through two different paths, where the first signal produces an output signal of -90° while the other signal, results in an output signal of -180° at Out (III). The superposition of the signal vectors (-90°, -180°), results in an output signal value of -150°. Thus, the phase magnitude of the signals obtained at each output port when Port 2 is fed are -270°, -30° and -150°. The equal phase difference results obtained when In (II) fed is +120°.\n\nThe input signal fed to In (III), produces an output signal of -360° at Out (I) when it passes through Coupler (I), Coupler (II) and Phase Shifter (I). The superposition of the signal vector of - 180°, -270 results in an output signal value of -240° at Out (II). At Out (III), output signal of -120° is produced from the superposition of the signals (-180°, -90°). The phase magnitude of the signal obtained at each output port when In (III) is fed are -360°, -240° and -120°. The output phase difference obtained when Port 3 is fed is -120°.23\n\n\nResults\n\nThe design of the SIW hybrid couplers shown in Figure 4 (a) is conducted using electromagnetic software, Computer Simulation Technology (CST) (The open-source version of this software is available at CST STUDIO SUITE Student Edition | 3DEXPERIENCE Edu (3ds.com). The phase delay of the coupler signal is 90°, and this is due to the quarter wavelength line at the coupler branch with 50-ohm impedance. The signal flow is depicted in Figure 4 (b), where the input signal is equally split to each respective output ports. In this design, the W aperture dimension controls the value of the coupling to be 3 dB. When a signal is fed into Port 1, it is distributed uniformly to Ports 2 and 3, while Port 4 is isolated because it does not receive power. When all ports are matched, power entering Port 1 is evenly distributed across Ports 2 and 3, with a 90° phase shift between these outputs. No power is connected to Port 4, because the signal is out of phase.\n\nEquation (7) can be used to determine the coupling factor, where the W aperture dimension is 2.78 mm, the pitch is 1mm, and the diameter of the air hole is 0.3 mm. The results of the hybrid are shown in Figure 5 in terms of return loss, S11, insertion loss, S21, coupling, S31, isolation, S41, and output phase difference. The simulation shows that the values of -27.35 dB for return loss (S11), -3.9 dB for insertion loss (S21), -3.2 dB for coupling (S31) and -26.54 dB for isolation (S41) indicate a high transmission efficiency. The coupling factor implies that the output signal is distributed evenly between the output ports, and that the phase difference between the two output ports is 93 degrees. The coupling equation (7) is shown below:\n\nThe phase shifter is designed in the BM to control the output beams radiated by the patch antennas. Three phase shifters are designed with phase differences of -90° and -180°, as shown in Table 1. In reference to the structure, phase shifter I and phase shifter II are designed with the hybrid coupler as the reference, while phase shifter III is designed with the respective transmission line as the reference. Each length dimensions of the phase shifter is controlled to produce accurate phase difference between the output ports, ∡ (P (4,3)) and the input ports, ∡ ((P (2,1)) which are -180° and -90°, respectively. The width of the microstrip transmission line used in the phase shifter has width dimension of 0.7826 mm, indicates 50 ohms impedance. The matched impedance of the transmission line is used to prevent losses occurring when integrated with the antenna array feed.\n\nThe proposed BM has a three input and three output matrices, where this system is designed to produce equal amplitude and phase at the output ports. Figure 6 illustrates the perspective view of the BM configuration, which has three elements for both the input ports and output ports. If the input ports are supplied with the signal, evenly distributed output signals are fed to each of the hybrid coupler and the phase shifter elements accordingly.\n\nThe phase shift between adjacent output ports, once the input port is fed with signal, δi in (8), is generated by:\n\nFor i = ± (1/2), ± (3/2), ± (5/2), ± (N-1)/2.\n\nThe performance of the 3 × 3 BM is studied using S-parameter simulation. The input and output return losses, Sii and Sii, are shown in Figure 7, where i represents the input ports and j represents the output ports. The results show that the return loss values are below -10 dB (theoretical) indicating a high transmission efficiency and the bandwidth fulfilling the requirement of the millimetre wave at 28 GHz (from f1 = 27.5 GHz, to f2 = 29.5GHz). The transmission amplitudes show values of –6 ± 3 dB for each Sij respective input-output port in Figure 8.\n\nThe SIW BM is connected to the planar antenna array to observe the radiation pattern. The element of the patch antenna is shown in Figure 9, where the dimensions are tabulated in Table 2. Figure 10 illustrates the return loss of the patch antenna at the interested bandwidth achieved below -10 dB. Three patch antennas are connected to the output of the BM, with λ0 /2 spacing between each other at 28 GHz, as illustrated in Figure 11 (a). When a signal is fed into the input ports, it is distributed with equal amplitude and progressive output phase shift to these three patch antennas. The antenna array spacing is set at λ0/2, which is equivalent to 5.357 mm at 28 GHz spacing, to provide a narrow beamwidth with reduced sidelobe.\n\nThe amplitude and phase excitation of each phase array antenna element are separately controlled to produce a radiated beam to the specific angle. The proposed structure, as seen at the center frequency, provides an equal power split from each input port, i (#1, #2, #3), to all output ports, j (#4, #5, #6). The current distribution is illustrated in Figure 11 (b,) when the input signal is fed into Port 1 (#1). The array factor can be influenced by the number of antenna elements, layout configuration, magnitude, minimum spacing, and relative phase. Equation 9 provides the equivalent phase shift across element, and 10 provides the BM beam direction, where d is the antenna distance and λ is the wavelength:\n\nThree beams with 0°, 30° and -30° beam directions are achieved by R. J. Maiiloux.24 The multibeam array antenna BM generates three different beams angles in its x-y plane, due to the progressive output from the BM. Figure 12 depicts the H-plane radiation patterns; when each of the three ports is fed individually, three beam outputs with maximum gains of 11.1 dBi, 9.06 dBi, and 10.4 dBi and angle directions of 0°, +27°, and -27° are generated.\n\n\nConclusions\n\nIn this paper, the BM has been designed using the SIW technique, where the width aperture is used to control the coupling value. The 3 x 3 BM, which is small and compact, can be used to steer the beam to the selected users, when integrated with the antenna arrays. The simulation of the SIW BM with the patch antennas shows promising results in terms of the return loss, transmission amplitude, gain, and the radiation pattern, without any compromise on the size. The system develops three beams to the angles of 0°, + 27° and -27°, with respective gains of 11.1 dBi, 9.06 dBi, and 10.4 dBi. The beamforming network of the BM with antenna array has a compact size of (45.93×21.5) mm2. Because the system is small and low loss, it is suitable for placement in the base station of 5G communication networks.\n\n\nData availability\n\nFigshare: The data for the design of 5G Millimeter-Wave Beamforming System using Substrate Integrated Waveguide is listed.\n\nDOI: https://doi.org/10.6084/m9.figshare.14883285.v218\n\nThis project contains the following underlying data:\n\n• Data file 1. (Hybrid S-Parameter)\n\n• Data file 2. (Hybrid S-Parameter (Phase))\n\n• Data file 3. (BM Return Loss S-Parameter (a) input ports)\n\n• Data file 4. (BM Return Loss S-Parameter (a) output ports)\n\n• Data file 5. (BM Transmission Amplitude, Sij input port 1)\n\n• Data file 6. (BM Transmission Amplitude, Sij input port 2)\n\n• Data file 7. (BM Transmission Amplitude, Sij input port 3)\n\n• Data file 8. (Patch Antenna S-Parameter)\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\nAuthor contributions\n\nNMJ: Conceptualization, Formal Analysis, Methodology, Software, Writing – Original Draft Preparation; AA/LN: Methodology, Software; ZY: Project Administration Supervision, Writing – Review & Editing, Validation, YY. Conceptualization, Formal Analysis.",
"appendix": "Acknowledgements\n\nThe authors wish to thank everyone, especially from Research Management Centre MMU Cyberjaya, SAP ID MMU/RMC/GRPROP/IR FUND/2020/16410, Faculty of Engineering, Multimedia University (MMU Cyberjaya), and Malaysia and Communication Systems and Network (CSN i-Kohza), MJIIT, UTM KL.\n\n\nReferences\n\nAkyildiz IF, Han C, Nie S: Combating the Distance Problem in the Millimeter Wave and Terahertz Frequency Bands. IEEE Commun. Mag. June 2018; 56(6): 102–108. Publisher Full Text\n\nJeon HB, Moon HJ, Kim SM, et al.: Demo. A Unified Platform of Free-Space Optics for High-Quality Video Transmission. Wireless Communications and Networking Conference Workshops (WCNCW), IEEE. 2020; 1–2.\n\nSun S, Rappaport TS, Shafi M: Hybrid beamforming for 5G millimeter-wave multi-cell networks Proc. IEEE Conf. Comput. Commun. Workshops, Honolulu, HI, USA. Apr. 2018.\n\nLuo Q, Zhu XW, Yu C, et al.: Single-Receiver Over-the-Air Digital Predistortion for Massive MIMO Transmitters with Antenna Crosstalk. IEEE Trans. Microw. Theory Techn. 2020; 68(1): 301–315. Publisher Full Text\n\nMishra D, Johansson H: Efficacy of Hybrid Energy Beamforming with Phase Shifter Impairments and Channel Estimation Errors. Signal Processing Letters IEEE. 2019; 26(1): 99–103. Publisher Full Text\n\nZhang N, Yin H, Wang W: Hybrid beamforming for millimetre wave massive MU-MIMO systems with IQ imbalance. Communications IET. 2019; 13(6): 776–785. Publisher Full Text\n\nPayami S, Sellathurai M, Nikitopoulos K: Low-Complexity Hybrid Beamforming for Massive MIMO Systems in Frequency-Selective Channels. Access IEEE. 2019; 7: 36195–36206. Publisher Full Text\n\nYang YK, Sim CY, Yang G: A novel 28 GHz beam steering array for 5G mobile device with metallic casing application. IEEE Trans. Antennas Propag. 2018; 66(1): 462–466. Publisher Full Text\n\nKim S, Yoon S, Lee Y, et al.: A Miniaturized Butler Matrix Based Switched Beamforming Antenna System in a Two-Layer Hybrid Stackup Substrate for 5G Applications. Electronics. 2019; 8: 1232. Publisher Full Text\n\nJizat NM, Yamada Y, Yusoff Z: Radiation Pattern of Array Antenna with the Dual-Layer Butler Matrix. 2020 IEEE International RF and Microwave Conference (RFM). 2020; 1–4.\n\nSakakibara K, Mizuno Y, Kikuma N, et al.: Millimeter-wave 4×4 Butler matrix for feeding circuit of multi-beam antenna using finline in multilayer substrate. 12th European Conference on Antennas and Propagation (EuCAP 2018). 2018; 1–4.\n\nHoward DD: Tracking radar. Radar Handbook. 2nd ed. ch. 18. Skolnik MI, editor. McGraw-Hill; 1990.\n\nPrakash V, Dahiya S, Kumawat S, et al.: Design of 4×4 Butler Matrix and its Process Modeling Using Petri Nets for Phase Array Systems. Progress In Electromagnetics Research C. 2020; 103: 137–153. Publisher Full Text\n\nYang Q, et al.: A Low Complexity 16 ×16 Butler Matrix Design Using Eight-Port Hybrids. IEEE Access. 2019; 7: 177864–177873. Publisher Full Text\n\nAlrushud K, Gómez V, Podilchak SK: Planar Quasi-End-Fire Antenna Design using SIW Technology for CubeSats and Other Small Satellites. 2021 15th European Conference on Antennas and Propagation (EuCAP). 2021; 1–5.\n\nChiu TY, Li CH: Low-Loss Low-Cost Substrate-Integrated Waveguide and Filter in GaAs IPD Technology for Terahertz Applications. IEEE Access. 2021; 9: 86346–86357. Publisher Full Text\n\nSun Q, Ban YL, Lian JW, et al.: Millimeter-Wave Multibeam Antenna Based on Folded C-Type SIW. IEEE Transactions on Antennas and Propagation. 2020; 68(5): 3465–3476. Publisher Full Text\n\nMd Jizat N: 5G Millimeter-Wave Beamforming System using Substrate Integrated Waveguide. figshare. Dataset. 2021. Publisher Full Text\n\nMohd Shukor NA, Seman N: 5G planar branch line coupler design based on the analysis of dielectric constant, loss tangent and quality factor at high frequency. Sci. Rep. 2020; 10: 16115. PubMed Abstract | Publisher Full Text\n\nChen XP, Wu K: Substrate integrated waveguide filter: Basic design rules and fundamental structure features. IEEE Microw. Mag. 2014; 15(5): 108–116. Publisher Full Text\n\nDeslandes D, Wu K: Design Considerations and Performance Analysis of Substrate Integrated Waveguide Components. European Microwave Conference. 23-27 Sept. 2002; pp. 881–884.\n\nBalanis C: Antenna Theory Analysis and Design. Wiley; 1997.\n\nWu B: 3X3 Butler Matrix and 5X6 Butler Matrix. Guangzhou, Guangdong 510700 Patent EP 3 024 297 A1, 25 05 2016.\n\nMaiiloux RJ: Phased Array Antenna Handbook. Artech House; 2005."
}
|
[
{
"id": "238985",
"date": "19 Feb 2024",
"name": "Suleiman Aliyu Babale",
"expertise": [
"Reviewer Expertise Antennas and Microwave devices such as Butler matrix",
"filters etc"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nCOMMENTS\nThere are a lot of existing designs on Butler matrix (BM). The author should clearly indicate the differences between the existing designs, and this proposed design. The explanations on the progressive output phase difference related to Figure 3 are not clear and look ambiguous. Please provide additional marks at the input and the output of each component for clarity. You may use ABCD…for this purpose. For example, when a signal is fed at In(I), it gets divided into two equal parts at B and C with an output phase difference of (90°, or 180°) or whatever.\nhttps://f1000research.s3.amazonaws.com/supplementary/73224/27c57381-90a8-4547-b1e4-710c3f2e8922.png\nAfter the explanation, kindly provide a summary table for the flow.\nIs there any mathematical model and theoretical background of the coupler used? If they exist, kindly provide them. As this is a special type of BM with 3 inputs and 3 outputs, what are the branch line impedances of the couplers used to form the BM? Place a strength marker for the surface current distribution for Fig. 4 as you did in Fig. 11. Also, if possible, readjust the arrow size to be more visible. Kindly explain the result of Figure 5 (b). Preferably, give the phase difference instead of the various phases. From Figure 7 and several others, how do you establish the theoretical value of -10 dB? No information on how the patch antenna was designed. What are the L’s and the W’s of table 2? Generally, more discussions are needed for all the results presented. There is a need for a comparison against other existing Butler matrices. Only simulation results were presented in this work. Kindly make fabrications, measure the results, and compare the simulated and the measured results. The references need to be updated.\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? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "244610",
"date": "27 Feb 2024",
"name": "Chun Geng",
"expertise": [
"Reviewer Expertise multibeam antennas",
"beamforming networks and mm-wave antenna arrays."
],
"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 novel 3×3 Butler matrix (BM) is designed employing substrate integrated waveguide (SIW). The proposed design requires only hybrid couplers and phase shifter without any crossover. In this BM structure, the SIW hybrid coupler is designed, with two phase shifters of -90°, and one phase shifter of -180°. The phase difference at each respective output port of the BM shows values of 0°, -120°, and 120°. Finally, by integrating the antenna array, a three-port multibeam antenna is realized. More comments are listed as follows.\nThe description of the transmission process of the Butler matrix from the input port to the output port is verbose and confusing, please express it clearly. The dimensional labelling in Fig. 4(a) is not clear and is not conducive to understanding, please make the dimensional labelling more visible. The surface current distribution in Fig. 4(b) is confusing, please revise the size of the arrow and a strength marker is needed to make it clearer. The title of the y-axis in Fig. 5(b) should not be “phase difference”, which does not correspond to the actual meaning of the solid line. The meaning of the diagrams in Table 1 is confusing, please replace them with representation of figures and explain the specific meaning of the figures, respectively. For the configuration of the 3×3 BM, the results of the isolation coefficients and the output phase differences corresponding to each input port does not show in this paper, please add the mentioned results if possible. The radiation performances of the patch antenna element are not given in this paper, please add and describe them if possible. The radiation patterns of the final multibeam antenna in curved form are not given in this paper, please add and describe them if possible. BMs have been developed extensively, please compare the proposed design with other similar BM designs to prove its value. Only simulated results were shown in this paper. If possible, please realize the fabrications and compare the simulated and the measured results. References in this paper need to be updated. Please centre all figures and tables and make all figures clearer if possible.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1311
|
https://f1000research.com/articles/10-1309/v1
|
22 Dec 21
|
{
"type": "Method Article",
"title": "Dynamic spectrum management using frequency selection at licensed and unlicensed bands for efficient vehicle-to-vehicle communication",
"authors": [
"Keshvinder Singh Randhava",
"Mardeni Roslee",
"Zubaida Yusoff",
"Keshvinder Singh Randhava",
"Mardeni Roslee"
],
"abstract": "Background: The exponential increase in pattern of vehicles on the roads demands a need to develop a vehicular infrastructure that may not only ease congestions and provide a better experience but also pivot the levels of safety among users. The development of wireless technology has made it convenient for machines, devices and vehicles to interact with one another. The efficacy of this wireless communications relies on utilising current and available technology to enable information to be shared efficiently. In the wake of the available advancement in wireless technology, a new dynamic spectrum management (DSM) in vehicle-to-vehicle (V2V) communication that coexists with the existing Long-Term Evolution (LTE) network to increase the throughput in V2V communication is proposed. This will provide some solutions to enable a more efficient vehicular infrastructure. Methods: This paper focuses on the utilization of DSM in V2V communications by selecting an appropriate frequency band through the selection of available licensed and unlicensed frequency bands for vehicles. Further investigations are done to identify the effect of interference in the dynamic spectrum by observing the path loss, SINR, and the throughput with various interfering users. Results: The results show that the performance of the proposed DSM augments a significant improvement in the overall throughput and the signal-to-interference-plus-noise ratio (SINR) value is reduced by up to 60% when compared to the fixed spectrum allocation. Conclusions: Although the dynamic spectrum is still affected by the interference from the existing cellular users, the throughput of the dynamic spectrum remains sufficient to transmit the information to other vehicles.",
"keywords": [
"Vehicle-to-vehicle (V2V)",
"dynamic spectrum",
"the fifth-generation technology standard(5G)",
"Long Term Evolution (LTE)",
"throughput",
"interference."
],
"content": "Introduction\n\nVehicle-to-vehicle (V2V) communication allows vehicles to interact and trade data or information directly with one another without the need of accessing a base station. This may involve data exchange with regards to speed, position and traffic environment.1 This method of communication correspondingly benefits users to avoid collisions, reduce traffic congestions and subsequently improves road safety.2 As the current wireless network technology moves from the fourth generation (4G) towards the fifth generation (5G),3,4 there lies a promising future for V2V communication in terms of improved latency, throughput and connections5,6 between vehicles. This enhancement in wireless network technology compels researchers to identify in detail the improvements to be made.\n\n\nLiterature review\n\nV2V communication is initially utilised in dedicated short-range communications (DSRC) through the exchange of information with each other.7 The DSRC generally works on the 5.9 GHz band8 of the radio frequency range and is powerful and efficient for vehicle communication that involves short to medium distance coverage. However, this technology does not offer high-speed communication.\n\nDue to the innovations driven by the 3rd Generation Partnership Project (3GPP), the most recent vehicle-to-everything are utilising the cellular networks. This network is known as Cellular V2X (C-V2X) to separate it from the wireless local area network (WLAN)-based vehicle technology.9 The 3GPP began to normalise work regarding cellular vehicular communication in 2014 during Release 14.10 This technology is known as Long-Term Evolution (LTE)-V2X since the functionalities of this technology relies on LTE networks. The C-V2X functionalities are extended to help 5G technology in the 3GPP Release 15.11\n\nEach technology has its assigned spectrum band where the users operate on the listened spectrum. Due to the expanding number of various kinds of wireless services and the number of vehicles on the road, the current fixed spectrum allocation policy such as dedicated short-range communications (DSRC) and LTE-V2X cannot cope with the growing demands of the wireless networks.12 Hence, the Federal Communications Commission (FCC) has proposed the usage of the underutilised spectrum and spectrum portions that are not in use by the user. The technology that can solve this problem is known as dynamic spectrum management (DSM) where it can combine a few bands in a wireless service.\n\nDSM is a technique subject to the theoretical concept in the communication network created to enhance the performance and proficiency of the network. Various studies have been done to explore the use of DSM by utilising diverse frequency ranges simultaneously in the vehicular network. Research13 was conducted in 2016 to demonstrate and analyse the efficiency of dynamic spectrum sharing among DSRC with the support of Wi-Fi systems. The author used the Poisson point process to dynamically construct a vehicular network where DSRC vehicles and Wi-Fi devices coincide and proposed the quality measures on the spectrum efficiency and data rate transmission. Results of this study indicate that dynamic spectrum allocation in the 5.9 GHz band improves the efficiency of the Wi-Fi network without excessively reducing the quality of the DSRC system.\n\nThe range optimisation for dynamic spectrum sharing using DSRC and 5G technology in V2V communication links was studied by Elias Alwan.14 Since DSRC provides a limited capacity for high-speed data, Alwan combined the usage of the 5G network to provide a high data rate in the V2V network. The channel link for this research work uses the free-space path loss model to investigate the link budget of the communication channel. Results from this paper show that the maximum data rate produced by this network model is 27 Mbps with a network coverage up to 500 m.\n\nHaibo Zhou et al.15 developed a dynamic sharing spectrum between 5G and DSRC frequency bands to prepare vehicular communication with massive system capacity while reducing the delay in communication and reducing cost. The idea proposed in this paper meets the developing expectations of vehicular communication services. However, this study does not consider that vehicles have high versatility and due to the heterogeneity of 5G, accomplishing an effective dynamic spectrum sharing is challenging in the real world. Hence, this paper makes realistic studies of the dynamic sharing spectrum of 5G and DSRC for the vivid experience in the vehicular communication network through the usage of available licensed and unlicensed frequency bands available. This paper will study the results of the path loss, signal-to-interference-plus-noise ratio (SINR), and the throughput with various interfering users.\n\nTable 1 shows that the LTE cellular network and mm-Wave technology may offer a high data rate in the vehicular network. Hence, this work will utilize LTE and mm-Wave technology that supports 5G to be used dynamically in the V2V communications to achieve better throughput in the network.\n\n\nMethods\n\nThis study got ethical approval from the Multimedia University Research Ethics Committee with approval number EA2832021.\n\nThis paper proposes an effective dynamic spectrum by utilising both licensed and unlicensed bands. The user’s spectrum selection is determined by the distance between the V2V pairs. Selection is made to determine the most suitable frequency band to be utilised in establishing a V2V communication channel. The proposed dynamic spectrum deals with the distance between the transmitter and receiver of the V2V link and selects either the licensed or unlicensed band that may significantly reduce the overall system interference while boosting the throughput in vehicular communication.\n\nThe licensed spectrum with a frequency band of 2.4 GHz is chosen since it is generally used by the LTE network. Similarly, the unlicensed spectrum band that uses the mm-Wave frequency band (5G) of 60 GHz16 is chosen. Due to the short coverage of 5G, the supporting LTE network is utilized to support a larger coverage area by providing communication between vehicles.17\n\nThe network system is designed in a hexagonal shape with a cell radius of 500 m (Figure 1). The network system is assumed to support both cellular and V2V communication in the network, where there exist n number of the existing cellular users which shall be considered as interfering devices in this paper, denoted as CUEs, and m number of vehicles doing local V2V high-capacity data exchange denoted as VUEs. It is assumed that all the vehicle and cellular user equipment is capable of supporting both licensed and unlicensed spectrum communications simultaneously. The value of the vehicle is more than the number of interfering devices, m >> n in this network setup.\n\nV2V = vehicle to vehicle; LTE = Long-Term Evolution.\n\nThe base station is placed in the middle of the network cell. The number of V2V pairs will increase gradually to analyse the algorithm of the network. The V2V pair will consist of one vehicle that will be a transmitter and another vehicle as a receiver. The cellular user and the V2V users are distributed uniformly over a hexagon cell area. In addition, it is assumed that all the devices in the network can support V2V mode and cellular mode in the setup.\n\nThe two frequency bands that are supported by the devices to transmit the data in the network are the licensed spectrum (LTE-V2V communication) and the unlicensed spectrum (5G cellular network supported by the mm-Wave technology).4 Additionally, the interfering devices that are connected to the vehicle are set to communicate using licensed spectrum, meanwhile, the V2V communication system will use either one of the spectrum bands depending on the best choice at that particular distance.\n\nThe path-loss for the proposed dynamic spectrum is designed by considering the free space, urban, and Line of Sight (LOS) models. It is also designed by considering the mm-Wave propagation models where the heavy oxygen absorption from the environment and heavy attenuation at 60 GHz is considered.18 The path loss in the transmission link between the V2V pair for long and short distances is modelled as:\n\nMeanwhile, the path loss due to the interfering users, CUE is modelled as:\n\nFor equations (1) to (4), the fc is in MHz and d is in metres. The constant value represents the shadowing effect of signal power fluctuations due to the surrounding obstacles. This dynamic spectrum V2V model is designed according to a Log-normal shadowing distribution and using a Rayleigh fast fading in the channel link.19\n\nSINR in V2V communication is obtained in this work to evaluate the performance of the spectrum and to compare the differences between the SINR fixed spectrum allocation of the unlicensed band and licensed band and the dynamic spectrum allocation in vehicular communication.\n\nThe received power signal is calculated by power transmitted minus path loss in the V2V link. The noise power density is stated as N0. It has a dimension of power over frequency, which is measured in watts per hertz or equivalent to watt-seconds. Meanwhile, the total power of the interfering devices received by the V2V receiver is label as ΣPInterferinglong and ΣPInterferingshort for long and short distances, respectively.\n\nThe Shannon capacity theorem is considered when calculating the throughput of vehicular communication. It characterises the maximum value of the successful message transmitted or the data capacity which is sent over any channel or communication medium. The system’s throughput for long and short distances is through equations below:\n\nBlicensed: bandwidth in Hz in the licensed spectrum.\n\nBunlicensed: bandwidth in Hz in the unlicensed spectrum.\n\nSINR: received signal power over the total noise power across the channel model.\n\nThe simulation is done using MATLAB version R2020a (RRID: SCR 001622) Communications Toolbox 2020 using the algorithm flow chart depicted in Figure 2. Alternative software that may be used are GNU Octave and SAGE (Phython SageMath). The parameters are based on Table 2 and the distance between the vehicle transmitter and receiver is calculated. The equations used after this is dependent upon the distances between the two vehicles. When the distance of the link is less than 15 m, the 5G unlicensed band setup is set up for the vehicle to transmit the data where the communication link now utilises the equations of PathlossV2VRXshort, SINRV2Vshort, ThroughputV2Vshort, which are equations (2), (6) and (8), respectively.\n\nAs the communication channel is set up using the LTE communication network, equations used to analyse the communication are equations (1), (5) and (7). Table 2 shows the parameter used in the simulation.\n\nThe code used in this paper is available from GitHub and is archived with Zenodo.21\n\nProposed performance test on the DSMin V2V communication.\n\n1: Initialise CUE=20, VUE=300;\n\n2: Generate the network setup model\n\n3: Calculate the distance between Vtx and Vrx\n\n4: if distance >15 % use licensed parameter\n\n5: f2 = 2.4 GHz,\n\n6: for V2V communication link\n\n7: Calculate PathlossV2VRXlong\n\n8: Calculate Received power,long\n\n9: For Interference link\n\n10: Calculate PathlossIntRXlong\n\n11: Calculate Interfering power,long\n\n12: Find SINRV2Vlong\n\n13: Calculate TV2Vlong\n\n14: else% if distance less than 15 m\n\n15: f1 = 60 GHz % use unlicensed parameter\n\n16: For V2V communication link\n\n17: Calculate PathlossV2VRXshort;\n\n18: Calculate Received power,short\n\n19: For Interference link\n\n20: Calculate PathlossIntRXshort\n\n21: Calculate Interfering power,short\n\n22: Find SINRV2Vshort\n\n23: Calculate TV2Vshort\n\n24: end\n\n\nResults and discussion\n\nThe network communication set up in the proposed DSM in V2V technology is simulated in Figure 3. The network model is designed in a hexagonal shape since it resembles the real-world communication coverage area.20 The radius of this system is set to 500 m. As mentioned previously, the number of vehicle users is set up more than the value of the interfering devices in the cellular network. The V2V receiver is denoted as ‘●’ meanwhile the V2V Transmitter is set as ‘►’ in Figure 3 where its location is fixed throughout the simulation. The interfering and V2V receivers are distributed uniformly over the network setup and the base station is located at the centre where it is symbolised as ‘o’.\n\nFigure 4 shows a significant improvement in the overall throughput in the network. The dynamic spectrum combines the technology of LTE and 5G in the vehicular communication network based on distance. Hence, there is still a throughput should the distance be more than 15 m as the proposed dynamic spectrum will utilise the LTE technology to expand the coverage area while maintaining a decent throughput in the channel. If the graph is focused at one point where the distance between the transmitter and receiver is 10 m, it can be observed that the throughput of the proposed dynamic spectrum is 224.5 Kbps, followed by the throughput of the unlicensed spectrum 168.1 Kbps and the licensed spectrum 72.44 Kbps, which denotes that the throughput of the dynamic spectrum suggests an improvement of 67% compared to the throughput in the licensed spectrum.\n\nFigure 5 shows that the static licensed spectrum offers a better path loss interference since the licensed spectrums are initially assigned for licensed users. Hence, the amount of interfering effects to this licensed spectrum is minimised compared to the other spectrum. Observing the point where the unlicensed spectrum is utilised, the unlicensed static spectrum suffered a higher path loss attenuation. The reason for this is because this spectrum was not initially assigned to V2V technology. It is actually an unutilised spectrum that people generally use when conducting experiments in the innovation of wireless communication technology.\n\n\nConclusion\n\nIn this paper, the DSM is implemented by choosing the more suitable frequency band based on the distance between V2V links to minimise the total system interference while increasing the throughput of the network. A simulation is performed using MATLAB R2020a to prove that the proposed dynamic spectrum guarantees improvement from the existing fixed spectrum allocation. Results show that the SINR of the proposed dynamic system is reduced by up to 60% compared to the unlicensed spectrum. It is also observed that the throughput of the proposed system shows a significant improvement of up to 67% compared to the licensed spectrum allocation. Towards the end of this paper, the effect of interference is studied in the dynamic spectrum. Through the graph, it can be observed that the interference power becomes higher as the distance between the transmitter and receiver is higher and this interference can be influenced by the number of interfering devices. Despite this, it can still provide sufficient throughput for the vehicles to share the information between them.\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\nSoftware availability\n\n\n\n• Source code available from: https://github.com/kesh3141/V2V-Comms_5\n\n• Archived source code at time of publication: https://doi.org/10.5281/zenodo.5760098.21\n\n• License: The GNU General Public License v3.0",
"appendix": "References\n\nU.S. Department of Transportation: Vehicle to Vehicle Communications for Trucks.2014; p. 2.\n\nLi B, He D, Feng Y, et al.: Spectrum Resource Allocation Scheme for Alarm Information Delivery in V2V Communication. IEEE Veh. Technol. Conf. 2018; vol. 2018-August pp. 0–4. Publisher Full Text\n\nStorck CR, Duarte-Figueiredo F: A Survey of 5G Technology Evolution, Standards, and Infrastructure Associated with Vehicle-to-Everything Communications by Internet of Vehicles. IEEE Access. 2020; 8: 117593–117614. Publisher Full Text\n\nStorck CR, Duarte-Figueiredo F: 5G V2X Ecosystem Providing Entertainment on Board Using Mm Wave Communications. Proc. - 2018 10th IEEE Latin-American Conf. Commun. LATINCOM 2018. 2019. Publisher Full Text\n\nParvez I, Rahmati A, Guvenc I, et al.: A survey on low latency towards 5G: RAN, core network and caching solutions. arXiv. 2017; vol. 20(no. 4): pp. 3098–3130.\n\nEl Zorkany M, Yasser A, Galal AI: Vehicle to Vehicle ‘V2V’ Communication: Scope, Importance, Challenges, Research Directions and Future. Open Transp. J. 2020; 14(1): 86–98. Publisher Full Text\n\nKenney BJB: Dedicated Short-Range Communications (DSRC) Standards in the United States.2011; vol. 99(no. 7).\n\nGuo J, Balon N: Vehicular Ad Hoc Networks and Dedicated Short-Range Communication.2006; vol. 6439: pp. 1–56.\n\nMolina-Masegosa R, Gozalvez J, Sepulcre M: Configuration of the C-V2X Mode 4 Sidelink PC5 Interface for Vehicular Communication. Proc. - 14th Int. Conf. Mob. Ad-Hoc Sens. Networks, MSN 2018. 2018; pp. 43–48. Publisher Full Text\n\nE. U. Terrestrial: Evolved Universal Terrestrial Radio Access (E-UTRA); Overall description stage 2; (Release 10), document ‘TS 36.300 V10.2.0,’ 3GPP, 2011-11.2013; vol. 0.\n\nNaik G, Choudhury B, Park JM: IEEE 802.11bd 5G NR V2X: Evolution of Radio Access Technologies for V2X Communications. IEEE Access. 2019; 7: 70169–70184. Publisher Full Text\n\nGyawali S, Xu S, Qian Y, et al.: Challenges and Solutions for Cellular based V2X Communications. IEEE Commun. Surv. Tutorials. 2020; 23: 1–1. Publisher Full Text\n\nXu W, Wu, Daneshmand, et al.: A data privacy-protective mechanism for WBAN. Wirel. Commun. Mob. Comput. 2015. Publisher Full Text\n\nGovindarajulu SR, Alwan EA: Range Optimization for DSRC and 5G Millimeter-Wave Vehicle-to-Vehicle Communication Link. 2019 Int. Work. Antenna Technol. iWAT 2019. 2019; pp. 228–230. Publisher Full Text\n\nZhou H, Xu W, Bi Y, et al.: Toward 5G spectrum sharing for immersive-experience-driven vehicular communications. IEEE Wirel. Commun. 2017; 24(6): 30–37. Publisher Full Text\n\n5G Automotive Association: An assessment of direct communications technologies for improved road safety in the EU.2017; (no. December): pp. 1–80. Publisher Full Text Reference Source\n\nChen S, et al.: Vehicle-to-Everything (v2x) Services Supported by LTE-Based Systems and 5G. IEEE Commun. Stand. Mag. 2017; 1(2): 70–76. Publisher Full Text\n\nSimić L, Riihijärvi J, Mähönen P: Can statistical propagation models be saved by real 3D city data?: A regionalized study of radio coverage in New York City. 2015 IEEE International Symposium on Dynamic Spectrum Access Networks (DySPAN). 2015; pp. 285–288. Publisher Full Text\n\nKompella S, Ephremides A: Stable Throughput Regions in Wireless Networks. 2014. Publisher Full Text\n\nNasri R, Jaziri A: Analytical Tractability of Hexagonal Network Model with Random User Location. IEEE Trans. Wirel. Commun. May 2016; 15(5): 3768–3780. Publisher Full Text\n\nRandhava KS, Yusoff Z, Roslee M: Vehicle to Vehicle Comms Using Licensed & Unlicensed Frequecies (MATLAB Communications Toolbox 2018a (License No:40598489).) [Data set]. Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "159120",
"date": "13 Mar 2023",
"name": "Muhammad Waqas",
"expertise": [
"Reviewer Expertise Wireless Communication",
"Vehicular 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 authors proposed the DSM in V2V communications by selecting an appropriate frequency band by selecting available licensed and unlicensed frequency bands for vehicles. Although the paper has merit, it requires extensive revision before indexing. My comments are given as follows.\n\nIn the abstract, the authors should not mention the headings. It should be in a continuous one-paragraph with word limits. No need to mention the headings.\n\nThe introduction section is not convincing. The authors need to mention the details in the introduction about the work done, the problem statement, the background and the contributions of the work.\n\nIn the literature, most of the related works are too old, for instance, most of the papers in the literature are from 2010 to 2015. There have been many advancements in this field since 2015. The authors need to update the related work section by citing up-to-date papers from 2020 to 2023. Some of the suggested references to be cited are given below. All the references are related to vehicular networks and are up-to-date:\n- Badshah et al. (2022)1 - Haider et al. (2023)2 - Ullah et al. (2022)3 - Munawar et al. (2022)4 - Abbas et al. (2022)5 - Waqas et al. (2022)6 - Ullah et al. (2021)7 - Ullah et al. (2021)8 - Haider et al. (2020)9 - Waqas et al. (2020)10 - Waqas et al. (2020)11\n\nThe algorithm is not in the standard format. The current format is not professional. I suggest seeing the published paper and taking the idea of how to write the algorithm in the technical papers.\n\nAll the figures must be revised. The current figures are not clear and don't attract the readers. The figures must be clear, clean and neat, and the text inside the figure should be in the same font and style as the text on the paper.\n\nThe authors also need to describe each figure clearly. The current version of the explanation is not convincing and doesn't provide the proper meaning of the work done by the authors.\n\nMore simulation results are needed to claim the work done.\n\nIt is better to write notations in the equation rather than writing the words.\n\nThe manuscript also needs an extensive revision to remove all the English mistakes, grammatical issues and typo errors.\n\nThe authors need an extensive revision of the paper and I will be happy to see the revise version of the manuscript.\n\nIs the rationale for developing the new method (or application) clearly explained? No\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": []
},
{
"id": "168198",
"date": "03 Apr 2023",
"name": "Mustafa Maad Hamdi",
"expertise": [
"Reviewer Expertise VANETS"
],
"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\nThere are some points to improve the article:\nAbstract\nNeed to mention the issue of this research paper and mention the value of results.\n\nThe abstract needs a rewrite, because the abstract must contain three points like: problem, method and results. Also, there are some problems with the grammar.\nIntroduction\nNeed more explanation in the introduction and mention the current issue and the objective.\n\nNeed to add the figure showing dynamic spectrum management (DSM).\nLiterature review\nNeed to mention the strengths and weaknesses for all studies.\n\nNeed to update all references and use more specific references in five recent years.\nMethod\nNeed to adding more explanation in methods and presented in clearly. Explain the steps of proposed method DSM with V2V ) and how observing the path loss, SINR and throughput with various interference user.\n\nNeed to adding flow chart. A flowchart would help make this article very simple to read and understand the proposed method (DSM) step by step.\n\nResults\nNeed to compare with benchmark.\n\nNeed to add more explanation in the results. Explain the figure of result in detail and discuss each value.\n\nAll figures in the results need to be redrawn again. They are not clear when the reader wants to see and read in this article.\nConclusion\nThe conclusion need to be rewritten and mention the future work. This conclusion must contain the contribution and the value of results. Also there are some problem with the language.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? No\n\nAre sufficient details provided to allow replication of the method development and its use by others? No\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1309
|
https://f1000research.com/articles/10-1306/v1
|
22 Dec 21
|
{
"type": "Research Article",
"title": "Perspectives on Open Science and Scholarly Publishing: a Survey Study Focusing on Early Career Researchers in Europe",
"authors": [
"Oleksandr Berezko",
"Laura M. Palma Medina",
"Giulia Malaguarnera",
"Inês Almeida",
"Agnieszka Żyra",
"Sothearath Seang",
"Mattias Björnmalm",
"Eva Hnatkova",
"Mathew Tata",
"Laura M. Palma Medina",
"Giulia Malaguarnera",
"Inês Almeida",
"Agnieszka Żyra",
"Sothearath Seang",
"Mattias Björnmalm",
"Eva Hnatkova",
"Mathew Tata"
],
"abstract": "Background: The value of Open Science (OS) for the academic community and society has been becoming more evident recently, especially during the COVID-19 pandemic. Nevertheless, significant challenges regarding its implementation arise that are likely to affect researchers, especially those in early career stages. Hence, monitoring early-career researchers’ views, knowledge, and skills on OS and related policies, is crucial for its advancement. The main aim of this exploratory study was to gain new perspectives regarding the awareness of and attitudes towards OS and related practices having in consideration geographical, economic and research career variables. Methods: The survey was conducted during May-August 2020 as part of a collaboration between Eurodoc and the Open Research Europe project. The data from the survey were analyzed by European region, Gross domestic product, Gross domestic expenditure on research and development as a percentage of gross domestic product, field of study, and career stage. Results: The awareness and positive attitude regarding OS, specifically among early-career researchers, is high in Europe. However, there are significant career stage group differences in views and knowledge about OS. Generally, awareness and positive attitude tend to increase with increasing career seniority. Regarding European regions, we spotted three main groups sharing similar awareness levels and attitudes: researchers in Western Europe - the most informed group towards OS; researchers in northern, central, and southern Europe - a moderately informed group with some minor differences; and researchers in eastern Europe - the least informed group, whose opinions deviate the most. Conclusions: We found that there is an “evolution of needs and focus” regarding scientific publishing: researchers in most European regions are in different stages of transition from the competitive to collaborative levels, while researchers in eastern Europe are largely beginning their transition to the competitive level.",
"keywords": [
"Early Career Researchers",
"Open Science",
"Open Scholarship",
"Open Access",
"Open Peer Review",
"Scholarly Publishing",
"Science Communication",
"Europe"
],
"content": "Introduction\n\nIn 2016, the European Commission (EC) presented a renewed vision for European research and innovation policy centred around the three O’s: ‘open innovation, open science and open to the world’,1 which has been continuously implemented by various groups of European science stakeholders such as universities, funding organizations, publishers etc.2 Open Science (OS) generally means transparent and accessible knowledge that is shared and developed through collaborative networks.3 OS is an umbrella term for various practices such as Open Access, Open Data, Open Methodology, Open Source, Open Peer Review (OPR), Open Reproducible Research, Open Education, Alternative Metrics, and Citizen Science.3–5 OS makes science more efficient, reliable, and responsive to societal challenges by opening up access to research data and results via new digital technologies and collaborative tools.6–8 Utilising OS, even if selectively and without commitment to total openness, brings many advantages to researchers including increased visibility, “liberation” from many perceived restrictions such as the need to produce only statistically significant results, and the fostering of creativity.9–11 The value of OS has become even more clear worldwide during the COVID-19 pandemic, which has highlighted the need for urgent access to scientific information, as well as the enhancement of scientific collaboration and knowledge-based decision making.12–14\n\nFor OS to become the dominant publication style, researchers need appropriate discipline-dependent skills training and professional development at all stages of their research careers.15 Moreover, the ideal time to build OS skill sets is early in the research career, especially since the benefits of OS for early career researchers (ECRs) are tangible (e.g., their research gets increased reliability and visibility) and should not be neglected.9,17 Thus, ECRs may be the key to definitively switching towards OS.16 However, for ECRs to become the change agents, significant challenges regarding widespread OS implementation (e.g. difficulties in adopting OS practices, access to tools and training, the time cost for additional requirements, and a lack of proper incentive and reward systems) must be addressed. In particular, these issues must be addressed during the current transition towards research openness due to the multidimensional and complicated nature of the changes needed.6,8,18 Widespread OS implementation requires a broader and more inclusive understanding of scientific contributions and expectations of productivity; thus a change in attitude needs to occur in academics at all levels, research organisations, and funders.9,19,20 For this to happen, regular and systematic monitoring of ECRs’ views, knowledge, and skills on OS and related policy adjustments at institutional, local, national, and international levels are crucial.\n\nPrevious studies have assessed the awareness of, and attitudes towards, OS or its specific components, such as Open Access publishing,21 OPR22 or preprints,23 but these were mostly focused on researchers within a specific scientific field e.g., social science, agriculture or health research24–26 or location, network or institution.27–29 Moreover, although some of these studies sought feedback from ECRs, their specific attitudes towards OS and new approaches to scholarly communication have been explored only to a limited extent due to the aspectual, field or location focused frames.9,17,24,26,30,31 In 2019, a transnational survey reported a significant degree of diversity in terms of scholarly communication attitudes and practices amongst ECRs in the eight countries studied,31 highlighting the need to study OS awareness on a multinational scale and across disciplines.\n\nIn recent years, research funding organisations, including those administered by the EC, have started introducing mandatory OS policies,5 as well as building tools and infrastructures intended to help researchers comply with the new requirements. With the vision to make the research outputs available to the public, the European Commission launched a new Open Access publishing platform, the Open Research Europe (ORE), in March 2021 for the beneficiaries of European Framework Programmes for Research and Innovation, Horizon 2020 and Horizon Europe. The ORE platform has been developed by F1000 Research as an Open Access publishing venue. The platform, using an innovative approach where publication and peer review are done independently, offers rapid publication of a wide range of research outputs under an open license, and OPR.\n\nEurodoc, the European Council of Doctoral Candidates and Junior Researchers, is a pan-European non-profit, volunteer organization, and federation of 29 national organisations, thus representing ECRs from European countries. In 2020, Eurodoc was among the organizations formally included as expert partners of ORE, with the mission to help steer the project and ensure that ECRs as stakeholders were reached. During the ORE platform development, Eurodoc members noticed a lack of comprehensive surveys on ECRs’ knowledge and attitudes toward publishing in OS encompassing the European sub-regions. Furthermore, previous analyses had rarely sought to address European countries' highly variable economic status, namely the financial resources allocated to science and how that relates to the awareness of OS in its broadest sense. Due to the fact that Eurodoc operates at the pan-European level and represents a wide network of member organizations acting in many European countries and regions, an opportunity for a survey at the European level emerged.\n\nConsequently, the survey was dedicated to gauging perspectives on OS and contemporary scholarly publishing, and was conducted between May to August 2020, as part of the collaboration between Eurodoc and the ORE project. The survey questions were developed by Eurodoc members (OS Ambassadors and OS Working Group members, all of whom were ECRs in diverse fields of study, located in 18 various European countries and actively advocating for OS) during online meetings between April and May 2020. The survey authors shared the draft versions and collected feedback from experts during the ORE Communications Group meetings. Experts’ comments were incorporated into the final version of the questionnaire. The survey was openly accessible to everyone willing to participate and was distributed via Eurodoc channels, its partners and members: national organizations of doctoral candidates and junior researchers in Europe (through social media, websites, newsletters, mailing lists, and personal contacts).\n\nThe main aim of this exploratory study was to gain new perspectives regarding the awareness of, and attitudes towards, OS and related practices within Europe. In addition, the aim of this study was also to investigate the hypothesis that differences in attitudes might arise in relation to factors such as economic indicators, research and development investment, the field of study, and career stage. Though the study was initially designed to contribute to the ORE project, it grew beyond this aim. We believe the results presented here may be relevant to anyone interested in understanding the role of ECRs in OS and can therefore be valuable to researchers, their representatives, funders and decision-makers at institutional, national, and the EU level.\n\n\nMethods\n\nAll respondents were informed about the background, aims and conditions of the survey through a dedicated web page that explained that all responses were anonymous and voluntary, and that all data would be kept confidential and evaluated anonymously in accordance with the Regulation (EU) 2016/679 (GDPR). Respondents were also informed that the survey data and results would be published. Written informed consent was obtained from the respondents (completion of the questionnaire was taken as consent to participate in the study). Ethical approval for the survey was waived by the Ethics Committee of the Lviv Polytechnic National University Academic Board. This waiver of approval was provided due to non-sensitive data obtained from the survey respondents. Choosing the EUSurvey platform as the questionnaire instrument allowed a high degree of privacy, as no email addresses, IP addresses, nor any other identifying data were collected alongside the responses. All free-text data was analysed separately from the main dataset.\n\nThe final survey version was available on the EUSurvey platform as an openly accessible online questionnaire. It was open between the 26th May and the 15th August 2020.\n\nIn order to maximize the number of responses, the survey was designed to be a brief to complete as possible, while still collecting meaningful data. The final version agreed by the study team took around seven minutes to complete and contained 35 questions: 14 of which were mandatory, four were optional, and an additional set of 17 dependent on answers to preceding questions.33 Most of the questions took the form of multiple choice, with free-text options available when choosing the response “Other”. Questions 1-2 gathered demographic data, whilst 3-7 and 9-11 assessed the academic and, specifically, the peer reviewing experience of participants, as well as their level of satisfaction regarding professional rewards for peer reviewing. Questions 12-16 examined how respondents communicate professionally and, in particular, disseminate their research outputs, as well as their level of satisfaction regarding the latter. The following questions then assessed knowledge/experience and general attitudes towards OS (questions 17-22) and OPR (questions 23-29). Question 8 and questions 30-34 sought feedback regarding participants’ motivations for choosing publishing venues, as well as attitudes towards the more “open” options and, specifically, ORE. The final question, 35, offered the opportunity to add any additional comments in a free-text format.\n\nThe total number of valid responses was 1187 (excluding two responses who were discarded as duplicates), which is comparable to other global and multinational surveys involving researchers.31,34,35 No exclusion was applied to career stage, age, gender, or field of study. However, we only selected answers from respondents in the countries belonging to the EU and/or Council of Europe for further analysis, according to the study aim. Survey organizers discussed the preliminary results in June 2020 during the online Eurodoc Conference.36\n\nThe data from the survey was analysed in consideration of five different grouping variables: European region, gross domestic product (GDP), gross domestic expenditure on research and development (GERD) as a percentage of GDP, field of study, and career stage.\n\nEuropean region\n\nThe survey was specifically aimed at studying the features of OS and publishing practices, and these are in turn directly influenced by the current research culture (i.e., behaviours, values, expectations, attitudes, and norms of research communities). As we wanted to explore further the potential impact of cultural differences on OS and the adoption of related practices, a division of Europe reflecting a “model of cultural spaces excluding national and political intentions while applying (…) critical factors for today's social, political and economic situations”37 was used. According to the above division, the responding countries were grouped into the following six regions:\n\n• Central Europe (Austria, Croatia, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Slovak Republic, Slovenia, and Switzerland)\n\n• Eastern Europe (Azerbaijan, Georgia, Russian Federation, and Ukraine)\n\n• Northern Europe (Denmark, Finland, Iceland, Norway, and Sweden)\n\n• South-eastern Europe (Bosnia and Herzegovina, Bulgaria, Cyprus, Greece, Romania, Serbia, and Turkey)\n\n• Southern Europe (Italy, Malta, Portugal, and Spain)\n\n• Western Europe (Belgium, France, Ireland, Netherlands, and the United Kingdom)\n\nGDP\n\nThe second variable these countries were grouped by, was the GDP per capita; an important indicator of national economic progress.38 As providing financial support to scientific research can be dependent on a country's economic status, wealthy states are typically in the position to spend more.39 This may also impact research culture in various countries and regions. Although relations between econometric and scientometric indicators might be indirect and need further investigation,39 the link between scholarly publication output of a given country (an indicator of the country's research activity) and GDP was reported in a particular field of study41 and across various research fields.40 For this variable, data from the World Bank42 was used (the GDP ranges were selected in an effort to create a balanced share of responses among the groups below). The currency used is international dollars; a hypothetical unit of currency that has the same purchasing power parity that the U.S. dollars had in the United States, at a given point in time,60 (in the case of these figures, October 2020):\n\n• 2,500-10,000: Azerbaijan, Bosnia and Herzegovina, Bulgaria, Georgia, Serbia, Turkey, and Ukraine\n\n• 10,000-25,000: Croatia, Czech Republic, Estonia, Greece, Hungary, Latvia, Lithuania, Poland, Portugal, Romania, Russian Federation, and Slovak Republic\n\n• 25,000-40,000: Cyprus, Italy, Malta, Slovenia, and Spain\n\n• 40,000-55,000: Austria, Belgium, Finland, France, Germany, Netherlands, Sweden, and United Kingdom\n\n• 55,000 or more: Denmark, Iceland, Ireland, Norway, and Switzerland\n\nGERD as a % of GDP\n\nSince GDP may not be a simple and clear indicator to interpret,43 GERD as a percentage of GDP44 was also used for the analyses, and is mentioned by several studies as one of the most important contributing factors towards impactful scientific knowledge generation.41,45 According to GERD as a % of GDP, countries were divided into five groups (the ranges were again selected with the aim of achieving a balanced share of responses among the five groups):\n\n• 0-0.75 %: Azerbaijan, Bosnia and Herzegovina, Cyprus, Georgia, Latvia, Malta, Romania, and Ukraine\n\n• 0.75-1.25 %: Bulgaria, Croatia, Greece, Ireland, Lithuania, Poland, Russian Federation, Serbia, Slovak Republic, Spain, and Turkey\n\n• 1.25-1.75 %: Estonia, Hungary, Italy, Portugal, and United Kingdom\n\n• 1.75-2.25 %: Czech Republic, France, Iceland, Netherlands, Norway, and Slovenia\n\n• 2.25 % or more: Austria, Belgium, Denmark, Finland, Germany, Sweden, and Switzerland\n\nField of study\n\nAs the ORE platform is aimed at Horizon 2020 program beneficiaries, the eight scientific areas defined in the H2020 programme guide for applicants46 were used for determining respondents' field of study, namely Chemistry, Economic Sciences, Information Science and Engineering, Environmental and Geosciences, Life Sciences, Mathematics, Physics, Social Sciences and Humanities, and Interdisciplinary.\n\nCareer stage (self-determined by responders)\n\nData was aggregated into the following categories:\n\n• Junior positions: student, doctoral candidate in higher educational institution, industrial doctoral candidate, junior researcher, and junior teaching staff member\n\n• Middle positions: researcher, independent researcher, middle teaching staff member, industry professional, and entrepreneur\n\n• Senior positions: senior researcher, and senior teaching staff member\n\nFinally, the survey contained questions to assess participants' perception of their career stage and various aspects of their professional experience, in particular peer-review articles and activities. This was important, in order to further characterize the sample by variables of interest such as OPR. Therefore, we can present additional analyses concerning perception of career stage (if respondents perceive themselves as ECRs or not) and scientific experience (if they had participated in a H2020 project, number of peer-reviewed research articles, number of research articles for which they have performed peer-review).\n\nAnalysis of categorical questions were assessed by evaluating the differences in the distribution of responses from each group by Pearson's Chi-squared Test. The analysis was performed on R v.3.6.0 using the method ‘chisq.test’ from the package stats. Stacked bar plots and radar plots associated with this type of questions were made in Microsoft Excel. Analysis of questions with numerical rating scales were analysed and plotted in GraphPad Prism® v. 9.1.0 and tested for differences between different categories with Kruskal–Wallis one-way analysis of variance followed by Dunn’s test for multiple comparison.\n\n\nResults\n\nRegion\n\nAs the survey was Europe-oriented and dissemination channels focused on European researchers, the vast majority of responders were located in Europe.33 We therefore considered only European countries’ responses (1162; 97.9%) into account for further analysis. The total number of European countries covered by the survey was 37 (Figure 1). The largest number of responses came from Ukraine (178; 15.3%), Spain (174; 15%), Germany (101; 8.7%), Italy (88; 7.6%), Denmark (80; 6.9%), Slovenia (66; 5.7%) and Poland (59; 5.1%).\n\nAlthough there was heterogeneity in the number of responses across countries, the representation by region was more balanced: central Europe (339; 29.2%), southern Europe (30; 25.9%), eastern Europe (202; 17.4%), western Europe (157; 13.5%), northern Europe (142; 12.2%), and south-eastern Europe (21; 1.8%). Finally, answers from all European regions were obtained, but the number of respondents from south-eastern Europe was substantially lower compared to the other regions. Consequently, we have abstained from performing further analysis including this region.\n\nGDP\n\nThe representation of country groups according to GDP was as follows: 2,500-10,000-214 responses (18.4%); 10,000-25,000-189 (16.3%); 25,000-40,000 - 330 (28.4%); 40,000-55,000-303 (26.1%); 55,000 or more - 126 (10.8%).\n\nGERD as % of GDP. The representation of country groups according to GERD as % of GDP was as follows: 0-0.75% - 232 (20%); 0.75-1.25% - 278 (23.9%); 1.25-1.75% - 179 (15.4%); 1.75-2.25% - 177 (15.2%); 2.25% or more - 296 (25.5%).\n\nAge\n\nAge was one of the mandatory questions: 5 respondents were under 18 years old (0.4%), 58 between 18 and 24 (5%), 403 between 25 and 29 (34.7%), 320 between 30 and 34 (27.5%), 293 between 35 and 44 (25.2%), 56 between 45 and 54 (4.8%), 18 between 55-64 (1.5%) and 9 over 65 years of age (0.8%). The majority of responders were between 25 and 44 years old (1016; 87.4%) and the average age was approximately 33.The respondents under the age of 18, considered themselves ECRs. Hence, we included their responses into the analysis; classifying them as First Stage Researchers (R1) according to the EURAXESS classification, meaning they are considered capable of at least “carry research under supervision”.61\n\nField of study\n\nThe division of respondents according to their field of study was as follows: Social Sciences and Humanities (304; 26.2%), Life Sciences (303; 26.1%), Information Science and Engineering (155, 13.3%), Physics (94, 8.1%), Interdisciplinary (88, 7.6%), Chemistry (79, 6.8%), Environmental and Geosciences (78, 6.7%), Economic Sciences (49, 4.2) and Mathematics (12, 1%). As the field of Mathematics had substantially fewer answers than all other categories, we abstained from using this category in further analysis.\n\nThe representation of various categories of researchers regarding their career stage was as follows:\n\n• Junior positions (799, 68.8%): student (44, 3.8%), doctoral candidate in higher educational institution (535, 46%), industrial doctoral candidate (15, 1.3%), junior researcher (177, 15.2%), junior teaching staff member (28, 2.4%)\n\n• Middle positions (238, 20.5%): researcher (168, 14.5%), independent researcher (29, 2.5%), middle teaching staff member (16, 1.4%), industry professional (20, 1.7%), entrepreneur (5, 0.4%)\n\n• Senior positions (87, 7.5%): senior researcher (64, 5.5%), senior teaching staff member (23, 2%)\n\n• Other (38, 3.3%)\n\nFinally, to further characterize the sample, we also assessed the respondents’ perception of their career stage and their scientific experience:\n\n• The majority of respondents (904, 77.8%) considered themselves ECRs, while 122 (10.5%) were unsure\n\n• 250 respondents (21.5%) participated in a Horizon 2020 research project\n\n• The distribution of respondents regarding the number of peer-reviewed research papers they had published was as follows: no papers (156; 13.4%), 1-5 (514; 44.2%), 6-10 papers (193; 16.6%), 11-20 papers (151; 13%), 21-50 papers (93; 8%), > 50 papers (55; 4.7%)\n\n• More than half of the respondents (606, 52.2%) had performed a peer review of research publications, either in their own name or together with more senior academics. Among those who’d done the latter, the division regarding the number of Peer reviews they had performed was as follows: 1-5 reviews (327; 28.1%), 6-10 reviews (93; 8%), 11-20 reviews (66; 5.7%), 21-50 reviews (67; 5.8%), >50 reviews – (45; 3.9%).\n\nOur analysis of the responses based on scientific experience demonstrates that most researchers typically begin peer reviewing after they themselves have published five or more research papers (Figure 2).\n\nBar plots display the percentage of responders with (Yes) and without (No) experience of peer reviewing among groups with different numbers of published research papers.\n\nIn this section of the survey, we investigated how familiar researchers were with OS and their attitudes towards it and its specific components.\n\nThis question explored the general awareness regarding OS, in order to determine the most and the least aware groups across different grouping variables. It was the “key” question, unlocking the other questions from the “OS section” for those who answered positively. The majority of respondents (76%) had heard about OS. However, we found differences across groups, mainly relating to the region of Europe, GDP, and GERD as % of GDP (Figure 3).\n\nRespondents were asked if they had heard of OS (answered by indicating either “Yes” or “No”). Cumulative bar plots display the percentages of reported awareness for (A) all respondents, or (B) based on European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test - results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThis question was available only for those who indicated that they had heard about OS (76% of the survey participants). It explored the level of OS knowledge among respondents, who were offered a 10-point scale for self-assessment, with the lowest mark (1) meaning “have just heard about it” and the highest (10) meaning “advanced expert.” The aim was to determine the most and the least knowledgeable groups across different grouping variables.\n\nWe found that the highest level of self-assessed knowledge of OS was in researchers in western European countries (Figure 4A), by a considerable margin. Equally, the highest knowledge level, based on GDP per region (Figure 7B), was found in the 40,000 – 55,000 range, with much of this group containing nations in western Europe. This trend shows that researchers from this region are most knowledgeable and positive in regards to OS; this trend is visible in other analyses below also). However, we found no significant differences between GERD as % of GDP categories. Among research disciplines (Figure 7D), the researchers in Information Science and Engineering and Interdisciplinary science reported the greatest knowledge of OS. We also found knowledge of OS appears to increase with increasing career seniority (Figure 7E).\n\nAbbreviations: Sc.: Science, Eng.: Engineering.\n\nThe graphs illustrate the mean and standard deviation of the responses from each group, with the y-axes representing the numerical rating scale and x-axes displaying the different categories assessed. General statistical significance was measured by Kuskall-Wallis test and is indicated above each panel. Stars indicate significance for multiple comparisons with Dunn’s test, with corrected p-values. * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001.\n\nThe next question sought feedback regarding participants’ general attitude towards OS, to determine the respective differences across various grouping variables and was, again, available only for respondents indicating that they had heard about OS (76%). Out of those, 90% (84% of the whole sample) agreed that OS “is generally a good thing”. We found no significant differences between any of the variables’ groups; at least 80% of respondents in any European region, GDP and GERD as a % of GDP ranges, the field of study, and career stage, kept the same belief. The biggest difference, although not significant, was found for field of study: representatives of Interdisciplinary and Life Sciences showed the most positive attitude, while representatives of Physics and Chemistry the least.\n\nThe percentages were calculated based on the classification of respondents. Cumulative bar plots show the results for (A) all respondents, (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test - results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nWe next explored which features and activities of OS were most important to respondents aware of OS, to determine which specific elements across different grouping variables are more appealing to researchers. We noticed relevant differences in the responses across the groups, the most significant in the region, GDP, and GERD as % of GDP; while attitudes towards the importance of reproducible research, and open and FAIR data varied the most (Figure 6, Table 1).\n\nIn general, respondents consider Open Access the most important feature of OS, followed by reproducible research and open and FAIR Data (Figure 6A). OPR in considered much less important. The rest of the features (Open Licenses for research outputs, Open Metrics and Impact, and Citizen Science) are not considered important by most of responders. Notably, reproducible research and open and FAIR data are considered much less important by respondents in eastern Europe (Figure 6B) and the countries within the 2,500-10,000 GDP rnage (Figure 6C) and less than 0.75% regarding GERD as % of GDP (Figure 6D). This was also the case for respondents in economics sciences (Figure 6E).\n\nRespondents could choose more than one feature. Radar charts display the results in terms of the percentage of total respondents of each category. Statistical differences were evaluated with a Chi-squared test and results are shown in Table 1.\n\nWe next explored what advantages respondents who were aware of OS, felt were offered by practicing OS, in order to determine the main incentives. Looking across the entire cohort studied, researchers in Europe indicated that the most important advantage of OS was “greater availability and accessibility of research outputs” (51.8% of responders). At the same time, we found differences across groups, the most significant in the European region, GDP, and GERD as % of GDP (Figure 7).\n\n“Greater availability and accessibility of research outputs” was less crucial for respondents in western Europe (Figure 7B) and the countries within the 40,000 - 55,000 GDP range (Figure 7C). “Greater reproducibility and transparency of research outputs” was much less important on average, but crucial for respondents in western Europe (Figure 7B), in the countries within the 40,000-55,000 GDP range GDP (Figure 7C), and in those spending the most on research (Figure 7D). Other options were considered much less important. Notably, the perceived importance of the “possibility of more transparent and rigorous peer-review process” tended to decrease with increased values of GDP (Figure 7C) and GERD as % of GDP (Figure 7D) and to grow with the career seniority (Figure 7F).\n\nRespondents were asked to select only one main advantage from a standard list of answers or select the option “Other”. This question was not compulsory. Percentages were calculated based on the total number of respondents per category. Cumulative bars plots show results for (A) all respondents, or classified based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test; these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThis question explored the main concerns respondents (only those aware of OS) had around OS, in order to identify the hurdles behind OS uptake. Researchers in Europe indicated that the “emergence of low-quality and false science” was their main OS-related concern (32.9% of respondents). Importantly, we found differences across groups; the most significant in the European region, GDP, and field of study (Figure 8).\n\n“Emergence of low-quality and false science” was particularly concerning for responders in northern and southern Europe (Figure 8B), the countries within the 55,000 or more and 25,000-40,000 GDP ranges (Figure 8C), and for respondents in chemistry, physics, and interdisciplinary (Figure 8E). It was less worrying for respondents in western Europe (Figure 8B), the countries within the 40,000 - 55,000 GDP range (Figure 8C), and for responders in social sciences and humanities and life sciences (Figure 8E). Notably, the popularity of this concern decreased with career seniority (Figure 8F). “Missing sufficient training, tools and infrastructures” was the primary concern for responders in western Europe (Figure 8B) and the countries within the 40,000-55,000 range (Figure 8C) and was more prevalent among respondents in information science and engineering, social sciences and humanities, and life sciences (Figure 8E). “Potential misuse of scientific research outputs” and “the public may misunderstand research outputs” were more concerning for respondents in eastern Europe (Figure 8B) and less wealthy countries in terms of GDP (the ranges below 25,000 - Figure 8C) and those spending the least on research (Figure 8D). This was also relevant for responders in economic sciences (Figure 8E). “More amount of work required from researchers” was less concerning for responders in northern and southern Europe (Figure 8B), the wealthiest countries in terms of GDP, (Figure 8C), and those in the 1.25-1.75% range (Figure 8D). This was also the case for responders in chemistry and economics sciences (Figure 8E). Importantly, the popularity of this concern increased with career seniority (Figure 8F).\n\nRespondents were asked to select only one main concern from a standard list of options or to select the option “Other”. This question was not compulsory. Percentages were calculated based on the total number of respondents per category. Cumulative bars plots display results for (A) all respondents, or classified based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test; these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nIn this section of the survey, we investigated how familiar researchers were with OPR and their attitudes towards it.\n\nThis question explored the general awareness regarding OPR to determine the most and the least aware groups across different dimensions. It was the “key” question unlocking the other questions from the “OPR section” for those who answered “Yes.” Most respondents had not heard of OPR (46% answered positively). We found differences across groups; the most significant in the GDP and European region (Figure 9).\n\nUnlike the rest, most responders in western Europe (Figure 9B) and countries within the 40,000-55,000 GDP range (Figure 9C) were aware of OPR. Respondents in southern and eastern Europe (Figure 9B) and countries within the 25,000-40,000 GDP range (Figure 9C) and in those spending below 1.25% of GDP on research (Figure 9D) were the least aware, which was also the case for the respondents in physics and economic sciences (Figure 9E). Awareness of OPR tended to grow with career seniority (Figure 9F).\n\nRespondents were asked if they have heard about OPR. Cumulative bars plots display percentages of awareness for (A) all respondents or based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test, these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThis question was available only for those who indicated that they had heard about OPR. It further explored respondents' experience passing through the OPR process to determine the level of engagement in this open practice from the author’s side. Only 22.6% of those who responded to this question had had this experience, and we found some differences among groups, the most significant in career stage and European region (Figure 10).\n\nExperience passing through the OPR process significantly increased with career seniority (Figure 10F). The most experienced responders were in eastern Europe and the least in northern and central Europe (Figure 10B) and countries within the 10,000-25,000 GDP range (Figure 10C). This was also the case for researchers in physics and information science and engineering (Figure 10E).\n\nRespondents were asked if any of their papers had been through OPR. Percentages were calculated based on the total number of respondents per category. Cumulative bar plots show the results for (A) all respondents, or classified based on (B) region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. This question was not compulsory. Statistical differences were evaluated with a Chi-squared test; these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThis question was again available only for those who indicated that they had heard about OPR. It further studied respondents' experience in OPR from the reviewer’s side. Even fewer respondents (17.6%) had had the experience of reviewing in OPR, and we found some differences among groups, the most significant in career stage and region again (Figure 11).\n\nAs in the previous question, the experience of reviewing research outputs openly significantly increased with career seniority (Figure 11F). However, unlike the previous question, the most experienced responders were in western Europe (Figure 11B) and in countries within the 40,000-55,000 GDP range (Figure 11C). The least experienced responders were in northern Europe (Figure 11B). Regarding the field of study, respondents in chemistry, physics, and social sciences and humanities had had the least experience (Figure 11E).\n\nRespondents were asked if they have been a reviewer in open peer review. Percentages were calculated based on the total number of respondents per category. Cumulative bar plots show the results for (A) all respondents, or classified based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. This question was not compulsory. Statistical differences were evaluated with a Chi-squared test, these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThe next question sought feedback regarding participants’ attitudes towards OPR compared to the conventional one to determine the differences across various dimensions. This question was available only for respondents indicating that they had heard about OPR. We found no significant differences between groups in any of the studied variables. Overall, 41.8% of those who responded to this question thought that OPR is better, while 45.3% answered “Not sure,” which matches the lack of OPR-related awareness in general.\n\nWe next explored what advantages respondents, who are aware of OPR, felt were offered by practicing OPR to determine the main incentives. Looking across the entire cohort studied, researchers in Europe indicated that the most important advantages of OPR were “encourages reviewers to be more tactful and constructive,” and “improves communication and understanding between authors, reviewers, editors and the broader community in general” (both options gained 35.0% of votes of those who answered this question). We found differences across groups, the most significant in the field of study, European region, and GDP (Figure 12).\n\n“Encourages reviewers to be more tactful and constructive” was selected less by respondents in eastern Europe (Figure 12B), the least wealthy countries in terms of GDP (Figure 12C), and those spending less than 1.25% of GDP on research (Figure 12D). This was also the case for responders in chemistry, interdisciplinary, and physics, while for respondents in environmental and geosciences and life sciences, this advantage was significant (Figure 12E). “Improves communication and understanding between authors, reviewers, editors and the broader community in general” was more important for researchers in northern Europe (Figure 12B) and those working in physics and interdisciplinary fields (Figure 12E). This advantage was less critical for responders in eastern Europe (Figure 12B), the least wealthy countries in terms of GDP (Figure 12C) and in those spending the least on research (Figure 12D). This was also the case for respondents in environmental and geosciences and economic sciences (Figure 12E). “Leads to more objective reviews” was much less critical for respondents in northern and southern Europe (Figure 12B) and those working in physics (Figure 12E). This advantage was more important for respondents in chemistry and economic sciences (Figure 12E). “Helps to detect reviewers' conflicts of interests” was most important for respondents in eastern and southern Europe (Figure 12B), the least wealthy countries in terms of GDP (Figure 12C) and in those spending less than 1.25% of GDP on research (Figure 12D). This was also the case for respondents in chemistry and social sciences and humanities (Figure 12E), as well as for senior researchers (Figure 12F). This advantage was less critical for respondents in central and western Europe (Figure 12B), in countries within the 40,000-55,000 GDP range (Figure 12C), and researchers in interdisciplinary and economic sciences (Figure 12E).\n\nRespondents were asked to select only one main advantage from a standard list of answers or select the option “Other”. This question was not compulsory. Percentages were calculated based on the total number of respondents per category. Cumulative bar plots display the results for (A) all respondents, or classified based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Statistical differences were evaluated with a Chi-squared test, these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThe next question explored the main concerns respondents (those aware of OPR) faced when practicing OPR to identify the obstacles in the OPR implementation. Researchers in Europe indicated that it “may disadvantage early-career researchers and be an advantage for established ‘big name’ researchers”. This was their main OPR-related concern (39% of responders), followed by “open reports may be less critical” (24%), “increased likelihood of reviewers declining to review” (21.8%), and “more amount of work required from reviewers” (10.8%). We found no significant differences between groups.\n\nThis question explored the level of perceived reward for peer reviewing among respondents, who were offered a 10-point scale for self-assessment, where the lowest mark (1) meant “not rewarded at all” and the highest (10) - “extremely rewarded.” The aim was to determine the most and the least rewarded groups (self-assessed) across different grouping variables. On average, the self-assessed level of feeling rewarded was 4.4.\n\nThe results are displayed as follows: (A) European region, (B) GDP, (C) GERD as % of GDP, (D) field of study, and (E) career stage. The graphs illustrate the mean and standard deviation of the responses from each group, where the y-axes represent the numerical rating scale and x-axes display the different categories assessed. General statistical significance was tested using the Kuskall-Wallis test and is indicated above each panel. Stars indicate significance for multiple comparisons using the Dunn’s test, with corrected p-values. * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001. The statistical test did not include the overall results as its main purpose was to detect differences between the different subcategories.\n\nThe number of answers to this question were substantially lower than the others (7.7% of responses), matching the generally low level of experience in OPR among European researchers. Hence, we abstained from performing analysis of these responses.\n\nIn this section of the survey, we investigated how familiar researchers were with Open publishing venues and their attitudes towards them.\n\nWe studied which factors respondents felt were decisive when choosing where to publish research outputs to identify desirable features of publishing venues. Most researchers in Europe still consider the journal impact factor the most important variable, followed by a high-quality peer review process. Moreover, we found significant differences across groups, especially in the European region and GDP (Figure 7, Table 2).\n\nThe results are displayed as follows: (A) results including all respondents, (B) region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. Respondents could choose more than one channel of preference. Radar plots display the results in terms of the percentage of total respondents of each category. Statistical differences were evaluated with a Chi-squared test and results are shown in Table 2.\n\nThis question explored the general awareness regarding open publishing venues to identify the most and the least aware group across different grouping variables. It was the “key” question unlocking the other questions from the “open publishing venues section” for those who answered positively. The majority of respondents were not aware (only 39.6% answered positively). However, differences across groups were found, the most significant in the GDP, region and GERD as % of GDP (Figure 15).\n\nAbbreviations: Sc.: Science, Eng.: Engineering.\n\nRespondents in western Europe (Figure 15B), in countries within the 40,000-50,000 GDP range (Figure 15C), and within the 1,25-1.75% range (Figure 15D) were the most aware of existing open publishing venues. Researchers in eastern Europe (Figure 15B), in the least wealthy countries in terms of GDP (Figure 15C) and in those spending below 1.25% of GDP on research (Figure 15D), were the least aware. Junior researchers were the least knowledgeable compared to their more senior colleagues (Figure 15F).\n\nPercentages were calculated based on classification of respondents. Cumulative bar plots display the results for (A) all respondents, or classified based on (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. This question was not compulsory. Statistical differences were evaluated with a Chi-squared test; these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nThis question was available only for those who reported being aware of open publishing venues. It further explored respondents' experience in OS practices to identify the level of engagement with existing open publishing venues. From the offered list of such venues, respondents were mostly experienced with PLOS One, but significant differences among groups, especially in the GDP, European region, and field of study were again found (Figure 16, Table 3).\n\nAbbreviations: Sc.: Science, Eng.: Engineering.\n\nAlthough some of the open publishing venues listed in the survey were more popular among respondents (Figure 16A), it is evident that generally, some groups of survey participants are much more experienced than others. Respondents in western Europe (Figure 16B) and countries within the 40,000-55,000 GDP range (Figure 16C) are the most experienced. In contrast, respondents in eastern Europe (Figure 16B), the least wealthy countries in terms of GDP (Figure 16C), and in those spending the least on research (Figure 16D) have much less experience. Regarding the field of study, experience with specific publishing venues might reflect their thematic focus. However, respondents in life sciences, interdisciplinary, and information science and engineering have more experience, while respondents in physics and economic sciences have less (Figure 16E).\n\nRespondents were given a set of open journals from which they could select multiple venues. They were given the option to add “Other” venues, but only individual venues that accounted for more than 5% of the responders are shown. Radar charts display responses by (A) all respondents, or classified by (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. In total, 393 (34%) respondents answered this question. The results are shown in terms of percentage of total respondents of each category. Statistical differences were evaluated with a Chi-squared test and results are shown in Table 3.\n\nThis question was again available only for those who reported being aware of open publishing venues. We explored which features of open publishing venues were reported as being the most important to identify the main motivations underlying their use. “Ability to address a wider audience” and “potential scientific impact and citations” were reported as the most important motivations, and we found important differences between categories, especially in the GDP, GERD as % of GDP, and European region (Figure 17, Table 4).\n\nAbbreviations: Sc.: Science, Eng.: Engineering.\n\nRespondents were given a set of motivations and could select multiple options. Results refer to analyses including (A) all respondents or classified by (B) European region, (C) GDP, (D) GERD as % of GDP, (E) fields of study, and (F) career stage. In total, 429 (37%) respondents answered this question. Radar charts display the results in terms of the percentage of total responders of each category. Statistical differences were evaluated with a Chi-squared test and results are shown in Table 4.\n\nAs the survey was initially developed to inform the ORE team, we explored the awareness level of this project across Europe. At the time of the survey, only 19.9% of respondents had heard about the ORE platform. Despite the general low awareness level, we spotted only minor differences across categories, namely in European region and Career stage (Figure 18).\n\nRespondents were asked if they have heard about the EC’s plans to establish ORE. Cumulative bar plots display percentage of reported awareness for (A) all respondents, (B) European region, (C) GDP, (D) GERD as % of GDP, (E) field of study, and (F) career stage. This question was not compulsory. Statistical differences were evaluated with a Chi-squared test; these results are shown below each graph. Degrees of freedom and sample size per categorization are shown between parentheses and p-values are shown between brackets.\n\nFinally, the way research findings are disseminated is changing with digitalization and today's communication technology. Indeed, it was demonstrated that higher engagement of the public with research happens through non-traditional routes such as social media.32 However, how research should be disseminated outside the standard route (academic journals or conference presentations) is debated. In particular, the use of social media should not substitute any validation that is obtained by peer-reviews and adequate editorial checks. Envisioning OS as “research knowledge shared (…) through collaborative networks”3 and with the aim of analysing the publishing practices, a section called “Scientific Communication” was included in the survey, questioning the new routes used by researchers to communicate their results.\n\nThis question explored respondents' experience in science communication through social media to identify the level of engagement with the most popular online social media platforms. From the offered list of platforms, responders reported being mostly experienced with ResearchGate. Significant differences were found among groups, particularly in GDP, European region, and field of study (Figure 19, Table 5).\n\nAbbreviations: Sc.: Science, Eng.: Engineering.\n\nUnlike the others, respondents in eastern Europe (Figure 19B), in the least wealthy countries in terms of GDP (Figure 19C), and in those spending the least on research (Figure 19D) rarely use Twitter to disseminate their research outputs but use Facebook and Academia more often. Respondents in western and northern Europe (Figure 19B), in the wealthier countries in terms of GDP (Figure 19C), and in those spending more on research (Figure 19D) tend to choose Twitter more often. Using LinkedIn to disseminate research outputs is more prevalent in northern Europe (Figure 19B). Respondents in social sciences and humanities, and economic sciences use Academia and Facebook more, while Twitter was more prevalent among life sciences and interdisciplinary respondents (Figure 19E).\n\nThe results are displayed as follows: (A) results including all respondents, (B) European region, (C) GDP, (D) GERD as % GDP, (E) field of study, and (F) career stage. Respondents could choose more than one channel of preference. Respondents were given the option to add “Other” social media used for dissemination, however these responses are not shown as each account for less than 5% of responses. In total, 1017 (88%) respondents answered this question. Radar charts display the results in terms of percentage of total respondents of each category. Statistical differences were evaluated with a Chi-squared test and results are shown in Table 5.\n\nThis question explored the level of satisfaction in regards to research outputs dissemination through social media channels, in order to determine the most and the least successful groups in this regard. Respondents were offered a 10-point scale for self-assessment, where the lowest mark (1) meant “not satisfied at all” and the highest (10) was “extremely satisfied.” In general, respondents were moderately satisfied with disseminating their research through social media channels, and the reported average level was 5.3. We found no significant differences between groups.\n\n\nDiscussion and Conclusion\n\nResearch activity is growing year-on-year, alongside a meteoric rise in publications and the number of journals.47,48 Despite widespread discussion of the importance of OS practices for transparency, reproducibility, and evaluation of research outputs, as well as increased access to knowledge, the deployment of OS tools and practices remains limited.16 In the present study we sought to explore if general awareness of and attitudes towards OS would provide a potential explanation for its limited use. We therefore studied if and how ECRs currently use OS, their general knowledge and attitudes of OS, and then focused on OPR and open publishing venues.\n\nIn summary, the results of the survey suggest that the awareness level in Europe regarding OS in general, and specifically among ECRs, is high, and views about it are generally positive: more than three-quarters of responders have heard about OS, and 90% of those agree that “it is generally a good thing” (Figure 3 and 5). Awareness about specific aspects of OS, such as OPR and open publishing venues is not so high though, with percentages under 50% for OPR and 40% for Open venues. The majority of respondents have not experienced OPR neither as authors or as reviewers, although career seniority was found to affect this. Responders report they still look at the Impact Factor when selecting a publishing venue. Importantly, significant differences were found in the awareness of and attitudes towards, various aspects of OS and science communication between researchers representing different European countries/regions, disciplines, career stage and scientific experience.\n\nIn regards to European regions, we spotted three main groups sharing roughly similar awareness levels and attitudes towards OS, as well as common science communication patterns: researchers in Western Europe - the most informed and positive group; researchers in Northern, Central, and Southern Europe - a moderately aware and positive attitude within this group, showing some minor differences; and researchers in Eastern Europe - the least informed and the most negative attitudinal group. Overall, opinions of researchers in Eastern Europe deviated the most from the rest of the respondents. One explanation is that this might be caused by these countries not being directly affected by EU policies, as well as being the lowest income area included in the study (GDP) and having the lowest level of investment in research (GERD & GDP). Another factor may be post-Soviet inertia (preserved negative and obsolete aspects of the previous period). This can manifest in a low level of replacement of aging human resources and outdated institutional mechanisms and equipment, which pose serious problems for the reforms in the research field such as OS principles implementation.49 This also correlates with a lower perception of academic integrity values in this region.50\n\nAlthough we found no direct correlation between OS and OPR awareness levels and the country’s wealth (GDP) and GERD as % of GDP, these variables do correlate slightly with the positive attitude towards OS. Indeed, the least wealthy countries in terms of GDP and those spending the least on research, demonstrate the lowest general OS awareness/positive attitude level. However, the results show that the opposite is not the case: researchers in Western Europe, but not in the wealthiest countries in regards to GDP, are the ‘OS champions’ of the continent, with the highest level of awareness and knowledge in this field, representing the “frontier of knowledge“regarding various OS features, and acknowledging advantages of open publishing venues. Also, their primary OS-related concern is “missing sufficient training, tools and infrastructures” rather than “emergence of low-quality and false science”; the main concern across all the other regions. It is still hopefully to note that widespread concern of the other regions, is a practical concern and might already be based on experience, and is focused on the implementation OS rather, than questioning the very idea of it (Figure 8).\n\nOA is considered the most important feature of OS by all the categories of responders, followed by reproducible research and open and FAIR data. OPR is considered much less important. Reproducible research is considered significantly less important by researchers in Eastern Europe and lower-income countries (even compared to the relatively low rating they gave to other OS features). This could be evidence of a weak research data management culture and may worsen the “reproducibility crisis” in these countries.51 Citizen science, open metrics and impact, as well as open licenses for research outputs are not considered important by all the categories of respondents. Notably, regardless of their category, the responders considered greater availability and accessibility or research outputs as the most important advantage of OS (which seconds the above statement about OA). The emergence of low-quality and false science was their main OS-related concern. A possible explanation of the above may be due to the recent awareness boost on OA, due to funders’ requirements in Europe. Notably, the Plan S principles, initiated by research funders (the cOAlition S), stated ten principles to make all scholarly publications mandatory accessible in Open Access journals, on Open Access platforms, or immediately available through Open Access repositories without embargo, and this to be effective by 2021. Therefore, Plan S may have contributed to improving the awareness towards the relevance of OA, and thus being the practice of OS most know among researchers. Another explanation maybe be the lack of knowledge about the meaning of other OS practices, which may be more evident with the number of respondents on OPR awareness and attitudes described in the next paragraph.\n\nResearchers in western Europe are again, the most aware of and the most active in OPR (together with researchers in countries investing more in research and development). This is compared to other European regions where more than 50% of respondents had not heard of OPR (the lowest awareness level, around 30%, was in southern Europe), with less than 20% peer reviewing research outputs openly (the lowest involvement levels were in northern and southern parts of Europe). Similarly, to the above-mentioned OS awareness and attitude analysis, we found no direct correlation between the OPR awareness level and the level of a country's wealth (GDP) or expenditure on research and development (GERD as % of GDP), except in those countries with the highest GDP and GERD as % of GDP. All regions shared approximately the same views regarding the advantages and disadvantages of OPR, as well as its general advantage over the conventional closed peer review (almost 42% of those who responded to this question believed that OPR was better, while more than 45% were unsure, thus reflecting the lack of knowledge on OPR). The responders considered the encouragement of reviewers to be more tactful and constructive as well as in improvement of communication and understanding between authors, reviewers, editors and the broader community in general, as the most important advantages of OPR. The main concern was that OPR may disadvantage ECRs and be an advantage for established “big name” researchers.\n\nIn general, European researchers do not feel particularly rewarded for their work as peer reviewers, and this might lead to additional challenges in the implementation of OPR. Hence, further research on establishing effective reward systems for reviewers (both monetary and non-monetary such as informal recognition52 or turning peer review into a measurable research output Publons-style53) is needed with onward analysis of the reported negative effects of such rewards, for-instance discouraging the most motivated and competent reviewers.54\n\nEvidence for a three-group pattern described above persists in regards to the awareness of and attitudes towards various publishing venues. When marking the most important factors to decide where to publish research outputs, researchers in western Europe once again demonstrated their commitment to OS and research integrity with a strong focus on high-quality peer review and OA, as well as noticeable demand for the rapidness of publishing and ability to publish all research outputs. Journal impact factors is still an important indicator for researchers in western Europe, but much less weighty than for their colleagues in northern, central and southern Europe. Researchers in these regions again has similar attitudes, with some differences. They are much less oriented towards OA (researchers in central Europe the most) and mainly focus on impact factor (researchers in southern Europe the most, while their colleagues in northern Europe the least). High quality peer review was also heavily weighted by these groups (researchers in northern Europe the most, while their colleagues in southern Europe the least), and rapidness of publishing and ability to publish all research outputs was much less valued.\n\nThe attitude of researchers in eastern Europe again deviate the most from the other regions; demonstrating a completely different set of priorities, such as indexing in major citation databases and publication fee, as well as paying significantly less attention to impact factors or high quality peer review, and OA. In addition, researchers in eastern Europe are the least motivated by features of open publishing venues and have incomparably less experience in using them compared to their colleagues in other European regions.\n\nAs most of the respondents in eastern Europe were from Ukraine, a view of the current state of the research publication infrastructure in this country helps explain their priorities. As of September 2021, according to Scimago, there were only 61 Ukrainian research journals indexed in Scopus (one of the two most important abstract and citation databases today55). These journals do not cover all research disciplines present in Ukraine and have relatively low impact indicators. For reference, Poland, a directly neighbouring state with a comparable population (44.4 million in Ukraine and 38 million in Poland as of 2019), had 451 journals indexed in Scopus as of September 2021.\n\nThe above analysis suggests an “evolution of needs and focus” regarding contemporary scientific publishing with the next successive levels: basic, competitive, and collaborative (Table 6). Each level reflects a particular stage of science communication infrastructure and related research culture development in a certain country or region, which defines a specific set of connected needs, goals, and success indicators.\n\nBy the “basic level,” we mean a relatively weak science communication infrastructure with a lack of quality publishing venues, which puts researchers' focus on participation, i.e., gaining the ability to use publishing venues, indexed in the most critical databases, for their research outputs dissemination. For example, the basic level can be currently observed in Ukraine. By the “competitive level,” we mean a relatively developed science communication infrastructure, characterized by a sufficient number of rival quality publishing venues, which put researchers' focus on competition, i.e., being able to get accepted in the most prestigious ones and thus prove their “excellence.” Countries on the basic level might be able to reach this level by developing their research infrastructures. For example, the “competitive level” can be currently observed in Italy and Spain. By the “collaborative level,” we mean a highly developed science communication infrastructure and research culture with a completely different set of priorities such as collaboration and societal impact, based on the principles of OS. Countries on the “competitive level” might reach this level by changing their research culture towards openness and collaboration and reforming research assessment systems while innovating their research infrastructure. As of December 2021, no country can be confidently listed here as an example of this level, but representatives of western Europe, such as Belgium and the Netherlands, are arguably the closest to it.\n\nAccording to the current study, most European regions (western, northern, central, and southern Europe) are in transition from the competitive to collaborative levels. In this regard, an essential question for eastern Europe and developing countries worldwide emerges: what is the best way to reach the “collaborative level” directly from the basic one avoiding the competition based on various bibliometric indicators?\n\nSeveral social media platforms are used to disseminate research outputs. ResearchGate was the most popular amongst all respondents, followed by Twitter in western and northern European countries, LinkedIn in northern European countries, Facebook in the eastern European countries, and Academia among researchers in the humanities and economics fields. Few researchers had reported using other online media for this purpose. ResearchGate was also the most popular platform for reaching out to other researchers for research-related advice; suggesting it to be a valuable forum for reaching scientists of any background. With social media growing more fashionable for both dissemination of research and researchers’ own branding, even in low and middle-income countries,56,57 these platforms represent a viable avenue for hosting and reinforcing OS practices.\n\n\nLimitations\n\nThe survey was generally disseminated among Eurodoc volunteers, who typically have an interest in European and international developments, and people interested in OS, meaning that the level of responders’ knowledge at the time of the survey might be somewhat higher than the average understanding amongst all researchers. The survey also lacked responses from certain countries, particularly in south-eastern Europe. This is not unexpected as Eurodoc has low representation in this area.\n\nGiven the field of studies, it is important to acknowledge the uneven distribution of respondents from various European regions among representatives of different research areas that significantly impacts the results. When analyzing the two biggest groups regarding the field of study (life sciences and social sciences and humanities, each consisting of 26.1% of all the responses), we spotted a substantial gap in several regions’ representation. For instance, among respondents from eastern Europe, only 23 (7.4%) were in life sciences and 80 (25.8%) were in social sciences and humanities. In contrast to this, among respondents from southern Europe 105 (33.9%) were in life sciences and 72 (23.2%) in social sciences and humanities, and among respondents from central Europe 82 (26.5%) were from life sciences and 64 (20.6%) from social sciences and humanities. For instance, regarding science communication through social media (Figure 19), the general pattern of ResearchGate popularity applies to all the categories. However, the most noticeable deviations (in the form of usage of other platforms) can be explained by the high percentage of researchers in eastern Europe among representatives of social science and humanities, and economic sciences (using Academia and Facebook more). Considering the above discussion of differences in awareness of and attitudes towards OS and online science communication among European regions, we recommend treating this section of the survey’s results with caution and organizing a new dedicated survey aiming at a more balanced geographical distribution or studying specific regions.\n\nRegarding the career stage, there is a positive correlation between the scientific experience of responders and their awareness and positivity towards OS and OPR. The latter correlation is stronger due to the limited engagement of ECRs in peer reviewing of any type (Figure 2). The above result could be explained by elements of a researcher’s career stage (particularly their seniority, age group, participation in a Horizon 2020 project, and publishing/reviewing activities) being reflective of the researcher’s experience, such as sophistication in science communication, and more extensive collaboration network. On the other hand, this might indicate an insufficient OS promotion and training level among ECRs and their engagement in various open practices. Although the above correlation is clear, the primary target group of the survey was ECRs (920, 77.6% of respondents) and researchers in junior positions (815, 68.7%). On top of that, the biggest group of respondents in senior positions were from eastern Europe (37, 41.6%). These limitations suggest that further research could be conducted on the differences in attitudes towards OS and its components among various groups of stakeholders with different experience (ECRs, researchers in middle and senior positions, and research librarians being arguably the most knowledgeable group). Further research could help to identify the most appropriate focus points for training and support on OS and incentive/reward systems for researchers, as was stated in Eurodoc input on UNESCO open science recommendation, where we asked for investments to human, educational, and infrastructural resources58 and which was also mentioned in the latest version of the recommendation.\n\nFinally, as this was an exploratory study, the statistical test procedures were not carried out in a hypothesis-driven manner (e.g. corrections for multiple comparisons), and interpretation of the results should bear this in mind.\n\n\nImplications and future directions\n\nIn our study, we sought to gain new perspectives on OS knowledge and motivation for its adoption amongst researchers, using a range of different dimensions relevant to demographics and background. Our results point to awareness levels of OS depending more on the European region (with the Western countries leading) than on the wealth and research and expenditure of the countries. Moreover, a more positive attitude towards OS practices was observed in researchers with higher knowledge on OS. We, therefore, postulate a program of “evolution of needs and focus” based on the level of OS knowledge and practices, currently categorizing by basic level, competitive level, and collaborative level (Table 6). Consequently, another question arises: what will the science communication landscape look like across the academic community of a specific country/region or globally after the “collaborative level” is reached, and what new predictable challenges might arise? Perhaps this will lead to a renewed focus on competition, but with a completely different set of indicators oriented towards teams and societal engagement rather than individual researchers. Also, advanced technology might become a more frequent player with the introduction of machine-learning approaches to support and assess various research processes and outputs.\n\nIn light of the survey, which corroborates previous findings on the topic of OS practices and adds further, we hypothesize that lack of OS awareness and negative attitudes may have implications for suggested changes in the current scientific culture, which is more focused on quantitative metrics and outputs than on quality and integrity of research. It is evident that OS practices are not yet integrated in research assessment procedures,59 thus constituting a burden for researchers and not a motivation, given the effort and time required for the research process. However, there is still a lack of studies regarding OS specific practices, such as OPR, across countries. Our study has clear implications for the design of OS implementation programs by focusing on training and introducing changes in the rewarding system through the revision of research assessment culture and procedures. Future studies should also monitor the researchers' approach to OS and science communication, given the debate raised during the COVID-19 pandemic about the dissemination of scientific outputs through the social media, in particular in their early stages, i.e., through preprints and enrolling citizens and policy decision-makers in this process.\n\n\nData availability\n\nZenodo: Eurodoc Survey on Publishing in Open Science 202033\n\nhttps://doi.org/10.5281/zenodo.5460097\n\nThis project contains the following underlying data:\n\n• Survey results, XLS\n\nZenodo: Eurodoc Survey on Publishing in Open Science 202033\n\nhttps://doi.org/10.5281/zenodo.5460097\n\nThis project contains the following extended data:\n\n• Copy of survey, PDF\n\nData are available under the terms of the Creative Commons Attribution 4.0 International.",
"appendix": "Acknowledgements\n\nWe would like to thank the Eurodoc OS Ambassadors 2019 cohort, the ORE project team (and especially the communications group members) for contributing, commenting, and shaping our questions in the survey. Many thanks to the Eurodoc members and administration of 2020 for helping us reach out to the respondents, who we also thank for taking their time to answer the present survey. Finally, we would like to thank the F1000Research team for supporting the present study publication.\n\n\nReferences\n\nMoedas C: Open Innovation, Open Science and Open to the World – A Vision for Europe Luxembourg: Publications Office of the European Union; 2016. Free full text\n\nMendez E, Lawrence R, MacCallum CJ, et al.: Progress on open science: Towards a shared research knowledge system: Final report of the open science policy platform. Publications Office; 2020. 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Nature. 2016; 533: 452–454. PubMed Abstract Free full text\n\nRestivo M, van de Rijt A : Experimental Study of Informal Rewards in Peer Production. PLoS ONE. 2012; 7(3): e34358. PubMed Abstract Free full text\n\nVan Noorden R: The scientists who get credit for peer review. Nature News. 2014. Publisher Full Text Free full text\n\nZaharie MA, Seeber M: Are non-monetary rewards effective in attracting peer reviewers?. Scientometrics. 2018; 117: 1587–1609. PubMed Abstract Free full text\n\nZhu J, Liu W: A tale of two databases: the use of Web of Science and Scopus in academic papers. Scientometrics . 2020; 123(1): 321–335. Publisher Full Text Free full text.\n\nDongn JK, Saunders C, Wachira BW, et al.: Social media and the modern scientist: a research primer for low- and middle-income countries. African Journal of Emergency Medicine. 2020; 10(Supplement 2): pp. S120–S124. Free full text\n\nCooper A: The use of online strategies and social media for research dissemination in education. Education Policy Analysis Archives. 2014; 22(88): 1–24. Publisher Full Text\n\nAlmeida I, Malaguarnera G, Hnatkova E, et al.: Eurodoc input on UNESCO Recommendation on Open Science.2020. Reference source\n\nHasgall A, Saenen B, Borrell-Damian L: Survey Doctoral education in Europe today: approaches and institutional structures. European University Association; 2019. Free full text\n\nWhat is an “international dollar”? World Bank Data Help Desk. The World Bank; Reference source\n\nResearch profiles descriptors. EURAXESS; Reference source"
}
|
[
{
"id": "118366",
"date": "20 Jan 2022",
"name": "Anca Hienola",
"expertise": [
"Reviewer Expertise Open science specialist",
"climate scientist"
],
"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 presents the results of a survey aimed at studying the awareness, practices, and attitudes towards Open Science (including publishing) in relation to the respondents’ field of study and career stage as well as the economic status (GDP and GERD as a % of GDP) of the respondents’ country of origin. The results provide an exhaustive picture of the culture of OS in various regions of Europe and make an important contribution to ongoing discussions around the challenges and cultural barriers faced by researchers, particularly ECRs, with respect to OS.\n1. Reduce the length. The article is well written and comprehensible, however very long and tedious to read from the beginning to the end. I strongly suggest reducing the volume of information within the article, especially the parts that are presented but not used in any way in the analysis process. For instance:\nIntroduction, paragraph 6 (starts with “Consequently…”) is not needed in this part. It would fit better in the “Survey process”, but anyway it does not bring any added value to the whole process.\n\nSurvey process, paragraph 2:Explaining the questions is not needed. One can check directly the survey.\n\nSurvey process, paragraph 3: the last sentence not needed.\n\nMethods and software used to process the survey data: I do not understand the need of this paragraph. The authors used a series of statistical tools listed in this section, but they are not analyzing the results based on them. Chi and p do appear in the figures, but not in the text and no explanation is given. As such they are redundant. The stats are also present in Tables 1-5 without any reference in the text (in the form of some sort of analysis). In addition, the software used for plotting is not important.\n\nGDP and GERD (in Demographics) I would rather have two plots than a text with a series of numbers\n\nAge (in demographics)- this is not used at all throughout the study. Consider Supplementary info.\n\nField of study (in Demographics): the representation of various categories of researchers regarding their career stage, again, it is not used anywhere in the study. Consider Supplementary info.\n\nTables 1-5. Consider Supplementary info but remove from the main text\n\nStarting with “Awareness of and attitude towards OS” down to “Which social media channels…”, almost every single section ends with a repetitive paragraph that fits much better in the corresponding Figure captions.\n\n2. Introduction, 1st paragraph. “such as the need to produce only statistically significant results”- do you refer here strictly to p-value? I don’t think the status quo has been challenged enough to lead to this kind of liberation. You could consider a more general approach like “only positive results”. This is just a comment.\n3. Introduction: please add a paragraph of a more clear explanation of what is new about this study compared to previous surveys.\n4. European region (page 5). The authors state that OS and publishing practices are influenced by the research culture and then divide Europe into regions based on a German article (which I cannot read) where they include Austria, Germany, and Switzerland among former communist countries (Croatia, Czech rep, etc). There are huge cultural differences between the two groups and most likely the results are somehow pulled up by the three German-speaking countries (I might be wrong). There are two possibilities: either explain in more detail why the selection of the regions was chosen as such, or try to divide Europe differently, as the history of the last 70 years drastically influenced the culture in Europe. As such, I suggest: Former Communist countries (now part of EU), Former Communist countries (not part of EU), Western Europe could include Austria, Germany, Switzerland, etc.\n5. Career stage (page 6). There is no one single definition for ECR. However, I think a definition should have been available for the respondents to avoid any ambiguity. (For example, European Geophysical Union defines An Early Career Scientist (ECS) as a student, a PhD candidate, or a practicing scientist who received their highest certificate (e.g. BSc, MSc, or PhD) within the past seven years). What was the idea behind finding out the “participants’ perception of their career stage? What was the rationale for not giving a clear definition of ERC?\n6. Throughout the text I have not seen any mention/analysis on the free text entries, if any, despite the fact that the authors mention at the beginning that the free text is analyzed separately. If any interesting free-text answers were provided, it would be good to list them in a table in a Supplementary file.\n7. Without any groups for non-ECRs, it is difficult to say that any of these analyses are specific to the ECR sections. A general phenomenon is common to the entire research spectrum.\n8. The rationale for selecting some of the topics investigated in the survey is unclear, namely open peer review and social media. Please provide justification for the topics selected for the survey. On the other hand, the results from the OPR and publishing could be the subject of a different article, in case the authors consider splitting the present one into two parts.\n9. Small typo: page 6 last paragraph, second row: southern Europe (30, 25.9%). It should be around 300 I guess.\n10. Try to be consistent throughout the text: some metrics are given as both numbers and percentages; some are only percentages.\n11. the last question of the survey is not addressed at all (what is the reaction of the respondents to ORE)\n12. The article would probably benefit from some practical recommendations, steps, changes at the European, national, and even institutional level in order to achieve “collaborative” science and faster integration of OS practices.\nI recommend the article be indexed after revision.\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?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "119105",
"date": "01 Feb 2022",
"name": "Noemie Aubert Bonn",
"expertise": [
"Reviewer Expertise Research on research",
"research integrity",
"research assessments",
"publication ethics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript provides a very impressive account of the perspective of European researchers on different aspects of open science. The manuscript compares answers by grouping respondents in different ways, such as groups based on the respondent affiliation country GDP, national investment in science, disciplines, seniority level, and geographic regions. The manuscript is interesting and easy to follow, and the associated data provide a rich basis for future work. For these reasons, I am confident that the manuscript will be useful to numerous researchers and am happy to see it published.\nWith that being said, there are some aspects of the manuscript which I believe could be improved, and there are a few mistakes that need to be addressed. Some of these issues are bigger than others, so I separate this review into three sections: The first section looks at main comments (A), which are the general comments that I found most important to raise. These are necessarily based on my personal views, and while they sometimes propose substantial changes to the manuscript, the authors are welcome to use their own judgement in deciding how and if they address these main comments. The next section covers specific comments (B), which target specific problems that are important to solve but rarely impact the entire message of the manuscript. Finally, I add a section for minor points (C), such as typos and small issues which I noted when reading. These are very small points, sometimes reflections for future work, and I add them to this review since I believe they can be useful to the authors even though many extend beyond regular peer review.\nA) Main comments:\n1. General purpose of the manuscript. The manuscript is certainly very rich and informative, providing a wide option of analyses to compare respondents on several categories. Nonetheless, I could not find an explicit explanation for the specific advantage that this detailed category division provides, and I would have liked the authors to expand on this more in the introduction and the conclusion of the manuscript. Although I am certain that this is clear to the authors, it is not clear from the manuscript what is the advantage of comparing regions, national wealth, research investments, disciplines, etc. Are these distinctions useful to understand where the investments would pay off the most? Are they useful to identify areas of needs that need more European support and funding? In the conclusion, the authors explain how the 'needs model' highlights a question: “what is the best way to reach the “collaborative level” directly from the basic one avoiding the competition based on various bibliometric indicators?”, yet this question is left unanswered. I feel that the specific need for analyzing the results in these categories and the expected use for the detailed regional findings should be explicitly stated in the introduction and the discussion of the manuscript.\n2. General conclusions of the manuscript: I found the details and descriptions in the results section very nice in letting the reader interpret the data on their own. Yet, when I reached the discussion section, I was sometimes surprised by the interpretation that the authors made of their data, and I would have interpreted the data differently. While I agree that my interpretation is no better than that of the authors, there are several instances where I feel that the manuscript could be rephrased to reflect the data more accurately.\nFirst, I was surprised by the authors’ main conclusion that “awareness level in Europe regarding OS in general, and specifically among ECRs, is high, and views about it are generally positive”. To me, knowing that almost one-quarter of respondents did not know about Open Science was quite a shock and it is a representation of a problem much bigger than what I anticipated. Consequently, I do not share the authors’ enthusiasm and think that this finding is, in and of itself, an urgent call for action and awareness raising among European researchers. The authors further mention that awareness is specifically high among ECR, but the survey found that ECR were less aware and less positive than more senior researchers on most occasions.\nSecond, I found the ‘discussion section’ to introduce a judgemental aspect in the awareness and perspectives of OS for which I do not see much value. For example, the authors describe Western European countries as “’OS champions’ of the continent” or as countries where “researchers demonstrated their commitment to OS and research integrity”, especially in comparison to eastern European countries. I feel that the survey enables the authors to say that awareness and experience with OS is more pronounced in Western European countries, but this does not necessarily imply commitment, especially not to research integrity which was not part of the survey. I believe that the conclusion should be reviewed to ensure that they are fully supported by the findings of the survey orin necessary, by associated literature. Along the same lines, authors sometimes single out specific countries as examples of research models (e.g., Ukraine, Spain, Italy, Belgium, Netherlands…). Since the findings from the survey are only reported on the aggregated regional form, I believe that these single country examples should be left out unless they can be supported by existing literature.\nFinally, the \"evaluation of needs and focus\" model constructed by the authors provides an interesting interpretation of the levels at which research cultures may operate, but the aspects it targets are not fully supported from the survey results. For instance, the survey did not assess whether specific regions focused mostly on quantitative metrics, and a general lack of knowledge of OS does not imply this perspective. I do not think that the authors need to change the model per se, but I believe that they should revisit the way they present it so that instead of saying “The above analysis suggests an “evolution of needs and focus” regarding contemporary scientific publishing with the next successive levels: basic, competitive, and collaborative” I believe that the authors should explain how they came about this particular needs and focus model based on the survey finding but also on existing literature.\n3. Statistical analysis details. I feel that some statistical results may be missing from the statistical analyses performed on the differences between the different groups in the main variable. Before anything, I want to emphasise that I have not used Chi-Squared statistics for a very long time and that my knowledge may therefore be rusty and incomplete. I would thus encourage the authors and the editors to consult with appropriate experts if my concern appears to be valid and to ignore this comment if this is something I misinterpreted. In short, the authors compare different groups of respondents on their distribution of responses. There are categories with either 3 groups (seniority), 5 groups (GDP and GERD as % GRP), or 8 groups (disciplines). Throughout the manuscript, the authors mention the ‘Omnibus’ Chi Squares, for example, the main tables of statistical results and underneath the grouping in figures, but I couldn’t see any post hoc results to detail the comparison between groups that are raised throughout the manuscript. Unless I am mistaken, the findings from these post hoc analyses and their associated significance should be included whenever a comparison is mentioned or at least included altogether in a table in supplementary materials. Additional details about these post-hoc tests should also be added in the appropriate section of the methods section.\n4. Overall length. The manuscript provides rich and detailed insights on the awareness and perspectives of selected European researchers on Open Science, but the overall length of the manuscript is very substantial. In many instances, adding significance symbols between groups in the figures could reduce the text from the results sections, leaving authors the opportunity to focus on the findings they see as most important to address. Also, related to the point I made about the general purpose of the manuscript (above), I wonder whether all questions really need to be displayed and detailed with all categories. Do the group differences provide concrete benefits on each of the survey questions? I leave it to the authors to decide how they address the length of this manuscript, but since the supplementary files contain the full data and could contain more figures, I thought that the readers may benefit more if the authors focus on the information that they find most relevant to address.\nB) Specific comments\nThe focus on Open Peer Review is very prominent in the survey, but it is unclear why this feature was selected over the many other aspects of OS (open data, open codes, etc.). The authors should explain a bit more why they chose to focus on this aspect rather than on other aspects of OS.\n\nThe same goes for the focus on social media and science communication. Since most of the paper looks at Open Science, the manuscript would benefit from an added context to explain why these specific topics were selected and what they mean in a survey on OS.\n\nOn P7, the authors mention that they kept respondents under 18 years old in the sample considering them as ‘First Stage Researchers’. This description should be added to the description of Junior positions on page 6. Along the same lines, it would be very useful if the authors specified what they mean by ECR in the beginning of the article. Are all of the aspects included in the ‘Junior’ category considered ECR? If yes, then why is it not called ECR instead of junior? (Note: It could be useful to be able to separate students at pre-doctorate levels from doctoral candidates to make a different category from pre-doctoral level students since these may be less aware of the publication system. I do not know if this is possible with the current data, so the authors can disregard this comment and consider it only as a note for future studies if it is impossible to do in this manuscript).\n\nP7, still on the age demographics: It is not clear why the authors report demographics from the age range which are not the same interval. For instance, 18-24 years old is an interval of 6 years, 30-34 years old is an interval of 4 years, 35-44 years old is an interval of 9 years, etc. I believe the intervals should be equal, or the inequality should be justified.\n\nThroughout the manuscript, the figure legends are intermingled with the text, making the reading difficult. They should be placed under the figure they represent, possibly in a legend format to avoid confusion.\n\nThe figures are very nice and useful, however, I often found myself missing information from them.\nFor all figures, make sure the order of the categories is coherent. For instance, GDP categories go from high GDP to low GDP but GERD as % GDP categories go from low to high. For figures 2, 4, 13 the axes should be detailed better to detail what they represent. For all figures: The colours should be adjusted to avoid highly similar colours (e.g., the blues in current figures) and if possible to allow colour blind reading. For the figures modelled like figure 3: Adding tick marks for the x-axis would be very helpful. For the spiderweb figures, the legends should clearly say that the figure shows the ‘percentage’ of respondents selecting this feature as… and indicate whether participants could select multiple features.\n\nOn page 9, the paragraph starting with “We found that…” addressed a question about knowledge on OS, but then goes on to say “researchers from this region are most knowledgeable and positive in regards to OS”. The introduction of positivity is very confusing here and should be kept in the respective section for that question.\n\nThis same paragraph also refers to Figure 7 and Figure 4, I believe ‘7’ should read '4' in most instances.\n\nOn page 10, the authors say “The next question sought feedback regarding participants’ general attitude towards OS, to determine the respective differences across various grouping variables and was, again, available only for respondents indicating that they had heard about OS (76%). Out of those, 90% (84% of the whole sample)” If I interpret this correctly, 90% of 76% would mean 68.4% of the whole sample, not 84%.\n\nAlso, a bit later in this paragraph, it is unclear what is meant by “kept the same belief”.\n\nFor the questions on OPR, the question about having had a paper peer-reviewed in OPR looks at all respondents who responded that they had heard of OPR, but it also includes respondents who declared that they never published a peer-reviewed paper since the N in figure 10 displays up to 516 participants but from the data file only 496 both published and heard of OPR.\n\nThe same goes for the question about having performed OPR, which included up to 514 respondents but from the data file, only 337 should have declared that they heard of OPR and had already performed a peer review.\n\nP18 on feeling professionally rewarded for performing OPR, it would have been interesting to have at least the general main group percentage of responses for that question.\n\nP20 I am unsure whether the authors can solve this issue, but it is confusing that the question asks about ‘having used’ open publishing venues while the description talks about ‘having experience with’. This could be interpreted either as having published in or read papers in, so some survey respondents may have interpreted this differently. For what concerns the manuscript, I think that the authors should stick to the term ‘Used’ to keep the message accurate.\n\nP23, the first paragraph constitutes more of an ‘introduction’ content than a ‘results’ section content. The authors should probably move this to the introduction and further detail why they selected these two axes of social media and OPR (as discussed above).\n\nP26 last paragraph the authors say “By the “basic level,” we mean a relatively weak science communication infrastructure with a lack of quality publishing venues, which puts researchers' focus on participation, i.e., gaining the ability to use publishing venues, indexed in the most critical databases, for their research outputs dissemination.” I wonder what the ‘lack of quality publishing venues’ mean here since most journals are international. Introducing the term ‘quality’ is also heavily charged, what is a quality publishing venue? Do the authors mean a journal that follows principles of OS, one with a high impact factor, one with a disciplinary reputation…? The authors should clarify this point.\n\nP28, last paragraph, the authors mention “Our study has clear implications for the design of OS implementation programs by focusing on training and introducing changes in the rewarding system through the revision of research assessment culture and procedures.”. It would be helpful to add a few examples of what these implications could mean in practice, if possible.\n\nC) Minor details (in order of appearance):\nI believe that making the data file a .csv rather than .xls would make it more interoperable, but I leave this in the hands of the authors and editors.\n\nThe quotation marks around “evolution of needs and focus” in the abstract are confusing for readers who have not yet made it to the discussion. The conclusion of the abstract is also difficult to understand since the conceptual terms of ‘competitive’ and ‘collaborative’ levels are not yet clear to the reader. If word counts allow, I would recommend that the authors add context and a bit of explanation to the conclusion of the abstract to help the reader understand these concepts.\n\nP3 second paragraph: “For OS to become the dominant publication style”, OS is much more than a publication style I believe. Maybe rephrase or change OS to OA if this is what is meant here.\n\nP3 last paragraph (starting with “Consequently, …”) this paragraph is already describing methods and I believe it would fit better in the methods section.\n\n(Personal thought, address only if deemed relevant) On top of P5, the authors discuss the potential impact of research culture on OS and practicing practices, and then go on to discuss their decision to separate European regions in different ‘cultures’. This paragraph seems to assume that regional cultures and research cultures go hand in hand. If this is the view of the authors, an additional sentence to indicate this link between country ‘cultures’ and research cultures could help the readers make this connection.\n\nOn P6, the last paragraph, there is a typo in the number of participants from “southern Europe (30; 25.9%)” should read something along the 300’s I believe. Small typo: P8 bullet point about the distribution of papers: 1-5 is missing the term ‘papers’\n\nP8, when describing those who peer-reviewed, the authors say “Among those who’d done the latter, the division regarding the number of Peer reviews they had performed was as follows: 1-5 reviews (327; 28.1%), 6-10 reviews (93; 8%), 11-20 reviews (66; 5.7%), 21-50 reviews (67; 5.8%), >50 reviews – (45; 3.9%).”. The percentages in this section seem to be the percentage among all respondents, not among those who performed a peer review. This should be clear by adding 'of all respondents' or by adapting percentages to this subgroup.\n\nIt took me some time to realise that the questions discussed were in fact the subtitles of the results section. This is a very minor detail, but maybe the authors could add a small sentence to say that each upcoming section will look at specific questions of the survey, and also mention that the questions and full range of responses are available in the survey printout included alongside the manuscript.\n\nP10 first paragraph, where it says “showed the most positive attitude” it sounds like positivity was rated on a scale. It would be most accurate to say ‘showed the biggest proportion of respondents with a positive attitude towards OS’ or something along those lines.\n\nP11, first paragraph. Is this also only with respondents who declared to know OS? Please specify.\n\nP11 second paragraph, small typo ‘rnage’ should be ‘range’\n\nP11, 5th paragraph, where the authors say that ““Greater availability and accessibility of research outputs” was less crucial for respondents in western Europe”; it would be more accurate to say that it was less often selected as the most crucial element for… P13 3rd paragraph, shouldn’t Figure 7 be Figure 13?\n\nSmall typo P18 just before table 2 there 1,25 should read 1.25.\n\nP20-21 the term ‘Open journals’ is a bit vague. Is it Gold, Diamond, is it open access, open data? Maybe a short description of the types of journals that were selected would be useful.\n\nP24 last paragraph (personal note): I am not a native speaker, so this may very well be my ignorance, but what does a ‘meteoric’ rise mean? Is it something sporadic or rather something intense?\n\nI hope that these comments may be useful to the authors. As mentioned above, the most important ones are the general comments, which can be addressed as that authors see fit, and the specific comments, which should be rather easy to address. The minor comments are mostly copy-editing and typos I noticed and thought I should as well mention as I went along the manuscript.\nI wish the authors the best of luck in revising their manuscript and I look forward to seeing the revised version!\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1306
|
https://f1000research.com/articles/10-1304/v1
|
22 Dec 21
|
{
"type": "Research Article",
"title": "Training strategies for the improvement of NATO Level 2 results for English Functional Level exams in the armed forces",
"authors": [
"Miguel Ángel Núñez Espinosa"
],
"abstract": "Background: As NATO (North Atlantic Treaty Organization) countries participate in many international missions and joint operations around the world, NATO considered it a necessity for personnel to be able to communicate in a common language. Therefore, one of the main tasks of the NATO multinational setting is the teaching and the assessment of languages. Consequently, there is a need for personnel to achieve the Standard Language Profiles (SLP). Each NATO country must develop SLP exams to achieve the required levels based on NATO STANAG (Standard agreement) 6001. If the examinees do not achieve those levels and the global results are unsatisfactory, NATO members can be affected by a reduction of financial support or the assignment to NATO postings. This study aimed to create a training strategies proposal (TSP) for personnel to achieve NATO L2. Methods: The study consisted of four separate studies: 1) Preliminary survey/interview of military personnel about NATO L2 training; 2) gathering data from NATO L2 exams after normal training; 3) gathering of data from NATO L2 exams after the TSP had been implemented; 4) Post-training survey. Data was collected from examinees over a period of six months or one year, using mixed data collection methods: surveys, interviews, and exam results. Results: A total of 50 examinees took part in the study. Results showed that the number of examinees who passed the NATO L2 increased after going through the TSP. Conclusions: The results show that the TSP, using newer methodologies and different techniques, improved NATO L2 results. The outcomes of this study will help to inform future training and education programs.",
"keywords": [
"Teaching English",
"Second language",
"English for a Specified Purpose",
"Military English",
"Training Strategies",
"NATO Level 2",
"Functional exams",
"CEF Level B2",
"Independent Users exams."
],
"content": "Introduction\n\nEnglish language teaching, learning, and testing carry high stakes not only for individual military members, but also for countries aiming to meet common language goals; this also applies to North Atlantic Treaty Organization (NATO) countries. Regarding the goal of Standard Language Profile (SLP) exams, military personnel from NATO countries aspire to join appointments that require NATO English Levels. Furthermore, there are many applicants seeking positions within NATO that also require a high level of English. SLP exams are based on testing four skills – listening, speaking, reading, and writing – following the STANAG 6001 criteria.a It is the responsibility of each country to establish its own training structure, design its syllabi and teaching materials, implement a testing framework, develop tests, and monitor training outcomes for these exams.\n\nGiven the scarcity of research in the training to achieve NATO Level 2(L2) within the specific field of the armed forces the present study bridges this gap by addressing the development of these four skills by using a new methodology, that tries to improve training and results. In order to do this, the study explores the benefits of using different techniques and newer methodologies that are adapted to NATO L2 exams. The results will help to clarify the gaps in training and education programs. The results of this study may have useful implications for training planners and tests administrators to achieve more satisfactory results. This study also undertook a literature review in order to obtain valuable sources to consult for the formation of the new training. Consequently, the overall aim of the study is to improve an L2 training program and to explore its effect in the field of NATO L2 within STANAG 6001 to try and reduce unsatisfactory results. This will then be tested to see if the improvements lead to better scores and skill levels.\n\n\nLiterature review\n\nThe Council of Europe has been active in the promotion of modern language learning and teaching since the signing of the European Cultural Convention in 1954. In 1989, member states agreed a set of issues on which it would be useful to organize programmes of research and development.b These were:\n\n• An enriched model for specifying objectives\n\n• Making use of mass media and new technologies\n\n• Bilingual education\n\n• The role of educational and cultural links, visits, and exchanges\n\n• Learning to learn and the promotion of learner autonomy\n\nThere has been a rapid expansion in the membership of the Council for Cultural Co-operation (a subdivision of the Council of Europe) following the political changes in Central and Eastern Europe around 1990. The Council has provided important guidelines for the reform and re-orientation of language teaching in new member states, as it was done previously in the principal project activity. The beginning of the 1990s was characterised by a general shift in focus. With the enlargement of the European Union, the importance of political, cultural, and scientific cooperation suddenly started to take centre stage. The Council resolved to make special efforts in national policies to promote a common understanding, in particular among young people, through cultural exchanges, co-operation in all fields of education and, more specifically, through teaching and training in the languages of other participating States.1,c\n\nA Frameworkd to provide support the above, was published in English (Cambridge University Press), French (Hachette) and German (Langenscheidt).\n\nThe Framework consists of a descriptive scheme setting out an analysis of language use and of the many ‘competences’, i.e., the shared knowledge and skills, which enable users of a language to communicate with each other. Wherever possible, these are separately calibrated with brief descriptors defining six levels of proficiency. Overall progress is also calibrated in this way. The Framework does not set out to prescribe standards but provides a basis for all involved in the teaching/learning process to reflect, plan, and communicate their decisions on objectives, methods, and achievements transparently and in compatible terms.\n\nAccording to the manual “Language Policy Unit, Strasbourg”,e the CEF of Reference for Languages provides a common basis for the elaboration of language syllabuses, curriculum guidelines, examinations and textbooks across Europe. It describes in a comprehensive way what language learners must learn in order to communicate in a language and what knowledge and skills they have to develop so as to be able to do so effectively. The description also covers the cultural context in which language is embedded. The Framework also defines different common levels of proficiency, which allow learners’ progress to be measured at each stage of learning and on a life-long basis. Following the official manual explanation, the CEF is intended to overcome the barriers to communication among professionals from different background (education, psychology, medicine, social work), and from the different educational systems in Europe. It provides the means for educational administrators, course designers, teachers, teacher trainers, and examining bodies to reflect on their current practice, with a view to situate and co-ordinate their efforts and to ensure that they meet the real needs of learners.\n\nGiving formal recognition to such abilities will help to promote multilingualism through the learning of a wider variety of European languages.\n\nThe uses of the Framework include:\n\n• The planning of language learning programmes\n\n• The planning of language certification\n\n• The planning of self-directed learning\n\n• Learning programmes and certification\n\nLanguage schools and certificate bodies evaluate their own equivalences against the framework. Differences of estimation have been found to exist, for example, with the same level on the PTE A (The Pearson Test of English Academic), TOEFL (Test of English as a Foreign Language), and IELTS (International English Language Testing System), and is a cause of debate between test producers. The CEF methodology has been extended to describe and evaluate the proficiency of users of programming languages when the programming activity is considered as a language activity.\n\nNATO is an intergovernmental military alliance between 29 countriesf and was established in 1949. It constitutes a system of collective defence and the members signed the agreement to mutual defence in case of an external attack. These countries have participated in many international missions and joint operations around the world. Because of that diversity, a common language is required to understand and be understood. Some of the missions required communication and cooperation with the rest of the armed forces members. Sometimes these missions were administrative duties, some were combatting missions. The need for linguistic communication was particularly important in order to avoid any misunderstanding because of the risk in case of language mistakes.g\n\nIn 2003, The Bureau for International Language Co-ordination (BILC),h which is the consultative and advisory body for language training in NATO, decided to release a document in order to standardize the language training and testing for all NATO members.\n\nThe Standard agreement was called STANAG 6001,i and it explains in detail the language proficiency levels that are considered the most appropriate in order to participate in joint international missions. Since that agreement, NATO members only deploy personnel to missions if they have certified the appropriate levels according with the standards. NATO countries strictly follow the Standard Agreements, and they allocate a large number of financial resources to language training.j But the training program is the responsibility of each country in order to achieve the SLP. They must establish their own materials and training plans. As Green & Wall (2005)2 reported in their study “some teams have taken a general English approach in their testing, others have incorporated a military flavour‟, and still others have used texts taken from military sources and tasks based on military scenarios”.\n\nThe language proficiency skills are broken down into six levels, coded 0 through 5. In general terms, levels may be defined as follows: Level 0, no proficiency; Level 1, survival; Level 2, functional; Level 3, professional; Level 4, expert; Level 5, highly-articulate/native.\n\nA series of plus (+) descriptions is provided. A plus indicator may be added to a base level for training, evaluation, recording, or reporting purposes, to indicate a level of proficiency that substantially exceeds a 0 through 4 base skill level but does not fully or consistently meet all of the criteria for the next higher base level. In general terms, plus levels may be defined as follows: Level 0+, memorized proficiency; Level 1+, survival+; Level 2+, functional+; Level 3+, professional+; Level 4+, expert+\n\nLanguage proficiency profiles are recorded using a sequence of 4 digits, with plus indicators if/when applicable, to represent the four language skill areas, and those skills will be listed in the following sequence: Skill L Listening; Skill S Speaking; Skill R Reading; Skill W Writing. This four-digit number will be preceded by the code letters SLP to indicate that the profile shown is the Standardised (S) Language (L) Profile (P). (For example: SLP 3321 means level 3 in listening, level 3 in speaking, level 2 in reading and level 1 in writing). The highest level of proficiency is level 5, and the lowest level of proficiency is level 0.\n\nCEF levels of proficiency are broken down mainly into three levels as Basic, Independent and Proficient users and each level is divided into two (1 and 2): A Basic User [A1 (Breakthrough); A2 (Waystage)]; B Independent [User B1 (Threshold); B2 (Vantage)]; C Proficient User [C1 (Operational Proficiency); C2 (Mastery)].\n\nTable 1 shows a comparison between CEF an NATO Language Standards in detail.\n\nSource: www.campaignmilitaryenglish.com.\n\n\nMethods\n\nFigure 1 shows the overall research design, which took place from May 2016 to November 2018. The research was split into four separate studies: 1) Preliminary survey/interview of military personnel about NATO L2 training; 2) gathering data from NATO L2 exams after normal training; 3) gathering of data from NATO L2 exams after training strategies proposal (TSP); 4) Post-training survey. Data was collected from examinees over a period of six months or one year, using mixed data collection methods: surveys, interviews, and exam results. Following Johnson & Christensen (2004),3 the interviews provided the participants’ perspectives that lie behind the proposed training before and after the NATO L2 exams. The mixing of the quantitative results and qualitative findings occurred in the final discussion, in which the study highlighted the quantitative results and the complexities that surfaces from the qualitative results.\n\nThe TSP was implemented between study 2 and 3 and will be discussed in more detail below. The TSP was either six-months or one-year. A variety of training strategies, a knowledge of student’s levels and the implementation of which strategies were best for any examinee, helped the trainer to know which program (six-months or one-year) would be the most effective for each examinee.\n\nThe study and the application of the TSP were based on a mixture of methods and approaches, including audiolingual method, direct method and physical response method.4 This mix of methods was done in order to meet the different needs of the examinees to achieve the NATO L2.\n\nThe participant selection was carried out by the trainer in accordance with the training strategies and the capacities of the group with the approval of the selected examinees.\n\nA total of 50 participants took part in the study and they started the first period of observation and analysis of the results after the first NATO L2 exams, but only 40 of them took part in the TSP. A total of 20 examinees took part in the six-month TSP and 20 took part in the one-year TSP. The participants were purposively selected to obtain a representative sample from different military categories and ranks: 10 officers (rank from Lieutenant to Colonel); 20 non-commissioned officers (e.g. NCO-visual leaders; Sergeant to Sergeant Major); 20 enlisted personnel (rank from private to all grades of corporal).k\n\nThe first two studies involved one-on-one survey administration method (giving tests and psychological instruments). This method is very time-intensive but can yield rich qualitative data related to the participant's cognitions, feelings, and behaviours, and a face-to face interview. It was completed by 50 examinees immediately before the NATO L2 exams and after having been trained applying some training programs.\n\nThe last two phases involved the one-on-one survey administration method followed by a face-to face interview. It was completed by 40 examinees immediately after the NATO L2 exams and after having been received the TSP.\n\nThis study examined factors most strongly associated with unsatisfactory results of the previous L2 training program. The study collected information from all 50 participants in face-to-face, researcher-given surveys.\n\nStudy 1 was carried out through a set of 20 open-ended questions (Box 1) to gather information about the examinees´ opinions after their NATO L2 training (TSP not applied) and before the NATO L2 exam. 50 participants took part in this study. The questions could be applied as a part of any other language training course evaluation, i.e. this is not restricted to NATO exams. Five of the questions were open-ended questions that ask the examinees to provide their opinion. The remaining questions were “scale and rate” close-ended questions (examinees were asked to rate the degree to which they are agree or are satisfied with) in order to quantify the problem by generating numerical data to be transformed into usable statistics (scale = 1-5; a higher score indicates the more the respondents were satisfied/agreed/important).\n\n1. How many SLP courses have you attended? Please explain the way the courses were designed and structured.\n\n2. What do you think about your current English level after the training and before the L2 exam?\n\n3. Do you think that L2 is a fair measure of your English level? Please explain in detail.\n\n4. Do you have any suggestions on how to train any of the four skills?\n\n5. What advice would you give to another examinee who is considering taking this training?\n\nThe “scale and rate” close-ended questions:\n\n1. How important is it for you to pass the L2 exam?\n\n2. Have you received information about the L2 exam?\n\n3. How motivated are you to study English?\n\n4. Did you learn English before you started attending the NATO L2 training?\n\n5. How do you perceive your training in order to take a test to achieve the NATO L2?\n\n6. Are you satisfied with the whole training?\n\n7. Would you think the trainers did a good job?\n\n8. Did you receive clear feedback from the trainer?\n\n9. Has the ongoing evaluation been useful for your motivation?\n\n10. Has the training been efficient in improving the four skills?\n\n11. Has the training been well-organized?\n\n12. Has the classroom been well-equipped with good technical tools and materials?\n\n13. Should the training last longer?\n\n14. Do you think that the training is better with fewer students per class?\n\n15. Do you expect to achieve NATO L2 after the training?\n\nExam data was collected from the participants (n = 50) after they had taken the L2 exam.\n\nThe elements, materials, and procedures for conducting the TSP were extracted from previous literature, and methods, military manuals (STANAG 6001 and BILC webl), books and essays. The training was personalized in accordance with the examinees needs. In this changing and competitive world, a good command of English can determine the candidates’ future in the military life.\n\nFor the proposed training program to be successful (NATO L2 achievement), the four skills (reading, listening, speaking, and writing) must be integrated in an effective way. These skills must be addressed in a way that helps examinees develop their language competence gradually. Listening and speaking are highly interrelated and work simultaneously in some real-life situations. So, the integration of the two skills aims at fostering effective oral communication in order to achieve NATO L2 in both skills. Reading and writing are also intimately associated. Developing students’ competencies in reading and writing requires exposing students to gradually challenging reading materials and writing tasks.\n\nThe TSP tries to make students read and write effectively. The proposed names for the training of each skill are outlined below:\n\n(1) Listening: “Listening fatigue stairs”: The training carried out a step-by-step program increasing the duration/intensity/length/level every month. The concept of “fatigue” is a subjective feeling that has a gradual onset of tiredness. Keeping in mind that the examinees normally lose concentration after 15-20 minutes (according to observation of the examinee by the tester), the proposed training carried out a step by step listening training increasing the duration/intensity/length/level every month. The objective was to adapt to this intensity in order to eliminate the fatigue.\n\n(2) Speaking: “Breaking the ceiling”: The main goal of the tester is to find the examinee’s limit of knowledge through intense training. The most important failure in examinees´ performance is that sometimes they get stuck, and they need the tester´s help to continue the oral proficiency interview (OPI). Consequently, some of them feel frustrated and they fail. Thus, one of the missions of the tester is to sample the examinee's language and elicit the highest level the examinee can reach. Some questions that are relatively difficult are intentionally asked in order to find the upper limits of the examinee's ability. The OPI allows a tester to assign a global rating that describes what a speaker can do with the language.\n\n(3) Reading: “Read, Breathe, Read, comprehend”: The training considers that the need to develop a habit to read is very important. The skill will be developed and acquired automatically once the habit has been established. The best and easiest approach is however, to start with making a small effort to read a piece of text a day. The second goal is the reading of a book every month. The training points out the reading and comprehension techniques recommended from our experience and close observation. The reading training proposal carries out a period of more than a year reading books (novels, short stories, fiction. Trainers must train the examinees in guessing the meaning of unknown words from the context. One of the proposals of the training is to read anything enjoyable (one way to assimilate information unconsciously and save it automatically) from which pleasure can be derived in addition to military matters, announcements, and discussions about everyday life, that will be essential in order to achieve NATO L2. Finally successful reading comprehension requires the integration and application of multiple strategies (memory, cognitive, compensation, metacognitive, affective, social and test-taking), and the training will focus the attention on those strategies, in particular, the test-taking strategy.\n\n(4) Writing: “Drafting and Multi-Wording”: The training focuses the attention on the importance of “Drafting” (transferring thoughts about the topic into main ideas to be developed, organizing the main ideas and concepts, creating and conceptual map and translating the ideas and thoughts into words, phrases, and sentences) and “Multi-Wording” (trying to find synonyms or play with chosen words and sentences to have a particular effect; a kind of brainstorming is included).\n\nAdditional information about what the TSP contained can be found in the Extended data.\n\nSix-month training: discarding the 10 examinees who achieved NATO L2 (see Study 2), 20 examinees with the best SLP results from the previous L2 exam were chosen. The criterion was the selection of examinees who achieved levels from L1 to less than L2 approx.\n\nOne-year training: discarding the 10 examinees who achieved NATO L2 (see Study 2) and the 20 examinees who were chosen to follow the six-months TSP training, the remaining 20 examinees were chosen. The criterion was the selection of examinees who achieved levels from L0, L0+ to less than L1 approx.\n\nExam data was collected from the participants (n = 40) after they had taken the L2 exam.\n\nStudy 4 carried out a survey to the participants that had been through the TSP training, but administering them a face-to-face survey (20 questions; Box 2). These were used to gather information about the examinees’ opinions after TSP training and after the NATO L2 exam.\n\n1. How long has your TSP training lasted? Please explain how it was.\n\n2. What do you think about your current English level after your TSP training?\n\n3. Do you think that the TSP training and NATO L2 exam are a fair measure of your English level? Please explain in detail.\n\n4. Do you have any suggestions about the TSP training?\n\n5. What advice would you give to another examinee who is considering taking this training?\n\nScale and rate questions:\n\n1. How important has the TSP training been for you to pass the L2 exam?\n\n2. Have you received more information about the L2 exam during the TSP training?\n\n3. How motivated are you to continue studying English?\n\n4. Do you think that you are ready to start L3 training?\n\n5. How did you perceive your training for sitting the L2 exam?\n\n6. Are you satisfied with the whole TSP training?\n\n7. Would you think the trainers did a good job?\n\n8. Did you receive clear feedback from the trainer?\n\n9. Has the ongoing evaluation been useful for your motivation?\n\n10. Has the training been efficient in improving the four skills?\n\n11. Has the training been well-organized?\n\n12. Has the classroom been well-equipped with good technical equipment?\n\n13. Should the training last longer?\n\n14. Do you think that the class must have fewer students per class?\n\n15. Do you expect to achieve L2 again after a month or a year?\n\nIn accordance with Study 1, five questions were open ended, and the rest were scale-and-rate (scale = 1-5; a higher score indicates the more the respondents were satisfied/agreed/important).\n\nPermission to conduct this study was sought and obtained from Escuela Internacional de Doctorado, Universidad Nacional de Educación a Distancia (UNED). Written informed consent to participate in the study was obtained from the participants prior to the study being conducted.\n\n\nResults\n\nMotivation, interaction, follow-up, and feedback instead of monotony and apparently redundant programs were important factors for the participants during L2 training. The responses of the “scale and rate” close-ended questions are shown in Table 2.\n\nSee Box 1 for more details on these questions. Numbers in red indicate the scale with the highest number of responders.\n\nThe study intended to quantify attitudes, opinions, behaviors, and other variables to draw relevant conclusions. This part is supplemented by the open-ended questions about motivations, expectations, and feelings (see Box 1 for more information on these questions).\n\nThe goal was to obtain a better idea of the examinees´ point of view on L2. It was shown that although examinees were very interested in achieving L2, they didn’t have enough information about the L2 exam. On the other hand, the motivation of the examinees to sit the NATO L2 exams was acceptable and most of them had experience in the preparation of NATO L2 exams. The majority of the participants weren´t confident with the English language and weren´t satisfied with the training, trainers, and the organization of the course. Moreover, the examinees felt that they needed longer courses with fewer students.\n\nFrom the open-ended questions, few of the examinees had attended other SLP courses and most of them thought that they had improved their level of proficiency after the training, but not enough to pass the L2 or to cover their expectations. It is particularly noteworthy that almost all of them felt that the program was redundant and monotonous.\n\nImportant variations were seen in L2 outcomes since there were different training programs. The showed that after various Functional Level trainings only 10 of 50 examinees achieved NATO L2. This is a poor outcome considering the fact that they were supposed to have an acceptable level of proficiency.\n\nThe TSP was divided into two kinds of training: six-months or one year, depending on the examinee level (after NATO L2 exam results mentioned above).\n\nAfter the six-month TSP training, 9 out of 20 examinees achieved L2.\n\nAfter the one-year TSP training, 6 out of 20 examinees achieved L2.\n\nTherefore, after TSP only 15 of 40 examinees achieved NATO L2. However, it can be interpreted that NATO L2 exam results did improve after the TSP training as 15 examinees who previously did not pass, passed after the TSP.\n\nResponses of the “scale and rate” close-ended questions are shown in Table 3.\n\nSee Box 2 for more information. Numbers in red indicate the scale with the highest number of responders.\n\nThe goal of this study was to carry out an in-depth analysis of the responses in order to have a clear idea of the examinees´ point of view. It was obvious that the examinees were very interested in achieving NATO level 2. The examinees stated that they were very satisfied with the TSP training and they had received enough information about the L2 exam. In addition, their motivation had been increasing and most of them were interested in improving their English learning processes. This puts a compelling case for a review of the effectiveness and efficiency of the TSP training.\n\nMost of the participants reported not being confident enough in starting L3 training because of the different levels of difficulty between both levels (NATO L2 and NATO L3). In relation to the TSP training, they were satisfied with the high level of the trainers, tools, materials, equipment and the TSP organization and program. On the other hand, some examinees felt again that they needed longer courses with fewer students.\n\nFrom the open-ended questions, both examinees that attend the six-month and one-year TSP training reported that they had improved their level of proficiency after the TSP training than before and that they have improved after the TSP training and enough to achieve L2 and to cover their expectations. It is particularly noteworthy that almost all of them felt that the TSP training program was motivational and interesting. Therefore, most of them recommended it to other examinees.\n\nHighlighting some examinees’ perspectives about the whole process:\n\n1. Most of them felt that TSP training had connected the L2 four skills learning and the learning of English language per se.\n\n2. They were aware of the importance of carrying out a long program with fewer students and a variety of activities despite the intense “listening fatigue stairs”.\n\n3. L2 achievement is a real challenge, and they need to be monitored by trainers to relate the examinee´s previous knowledge to their personal motivation.\n\n4. They need to feel able to take risks, without being frightened of making mistakes. Trainers must take up the challenge of searching for their best English.\n\n\nDiscussion\n\nThis study attempted to explore the application of the proposed TSP for the Acquisition of Functional Skills in English for examinees who wanted to achieve NATO L2 and for the assessment of the examinees’ point of view. The primary wish behind this study was to try and show the variations in L2 outcomes since there were different training programs. It is shown that the NATO L2 exam results after the TSP had improved. Therefore, the study intended to show that the unsatisfactory results because of the low rate of success (only 10 of 50 examinees achieved NATO L2 after the application of generic NATO L2 training) in order to achieve NATO L2 and the level differences among the examinees could be due primarily to the training program carried out.\n\nStudy 1: 50 participants took part in the survey and interview about generic NATO L2 trainings. The survey indicates that the motivation of the examinees to sit the NATO L2 exams was acceptable and most of them had experience in the preparation of NATO L2 exams. I would like to highlight the fact that most of them weren´t confident about themselves and they weren´t satisfied with the training, trainers, and the organization of the course. Moreover, the examinees felt that they needed longer courses with fewer students. It was shown that few of the examinees had attended other SLP courses and most of them thought that they had improved their level of proficiency after the training, but not enough to pass the L2 or to cover their expectations. It is particularly noteworthy that almost all of them felt that the program was redundant and monotonous.\n\nStudy 2: Of the 50 participants that took the NATO L2 exam, only 10 passed.\n\nStudy 3: Of the 20 participants that took the NATO L2 exam after the 6 month TSP, 9 passed the NATO L2 (45%). Of the 20 participants that took the NATO L2 exam after the one year TSP, 6 passed the NATO L2 (35%). Therefore, only 15 of 40 (37.5%) examinees achieved NATO L2 after the TSP.\n\nStudy 4: 40 participants took part in the survey and interview about the application of the proposed training (TSP). The survey indicates that the examinees were very interested in achieving NATO level 2. It is noteworthy that they were very satisfied with the proposed TSP training and the examinees´ reported that they had received enough information about the L2 exam. In addition, their motivation had increased and most of them were interested in improving their English learning processes. Most of them weren´t confident enough to start L3 training because of increased difficulty between NATO L2 and L3. The examinees’ p were satisfied with the high level of the trainers, tools, materials, equipment and the TSP organization and program. On the other hand, some examinees felt again that they needed longer courses with fewer students. The most important conclusion is that most of them thought that they had improved their level of proficiency after the TSP training.\n\nIn relation to the overall aim of the study, the results show that there is a real need for the application of other training in order to successfully achieve NATO L2 requirements. It is commonly known that it is very difficult for all examinees with different levels to achieve 100% satisfactory results. Therefore, the TSP could help NATO L2 trainers and private academies to make changes and improvements.\n\nThe data collected showed that only 10 of 50 (20%) examinees achieved L2 after the application of some Functional Level trainings, while 15 of the remaining 40 (37.5%) examinees achieved L2 after the proposed TSP training. It is shown that there are examinees who show a greater improvement and other examinees who show a sign of a modest improvement. It therefore follows that the NATO L2 exam results after the TSP have improved considerably (from 20% to 37.5% success rate).\n\nIn accordance with the results obtained from the surveys of the examinees, the most important differences between the two training styles could be the increased motivation, interaction, follow-up, and feedback of the TSP instead of monotonous and redundant programs (according to the information gathered in Studies 1 and 4). Consequently, other points to consider concern the application of some Functional Level training in order to achieve NATO L2 due to the fact that they have not been submitted to significant revision in recent years.m\n\nFinally, the study didn´t demonstrate if there is any benefit from the implementation of the proposed TSP program to any civilian scope (CEF). But given the fact that there are similarities between both fields (military SLP exam and CEF requirements), it could be concluded that the TSP training could be applied to other fields. Future studies should be done to assess if the TSP training is useful in the civilian comprehensive testing system, such as the Test of English as a Foreign Language (TOEFL), the International English Language Testing System (IELTS) or The Cambridge Assessment of Spoken English (CASE).\n\nIn conclusion, it is important to consider the results of the study and the TSP training outcomes in order to find an appropriate training which could be useful not only in NATO testing system but in all comprehensive testing systems. The need to find a common training could be the starting point for critically examining the teaching/learning testing systems for better planning and the development of an effective implementation at all levels of proficiency.\n\n\nData availability\n\nDue to the restrictions surrounding military data records, the underlying data for this study cannot be provided. This includes the data survey data in Studies 1 and 4 and the NATO L2 scores in Studies 2 and 3. Researchers wishing to access this data should liaise with the corresponding author (mnunesp@et.mde.es), who will facilitate obtaining the data through military channels (Spanish Ministry of Defence).\n\nDANS: Training for NATO level of English language, https://doi.org/10.17026/dans-xzh-54fv.5\n\nThis project contains the following extended data:\n\n• A proposal of some training strategies for the improvement of NATO Level 2 results in the Functional Level exams in English in the field of the Armed Forces.pdf (official results from all participants, the summary of the surveys and the follow up during the training)\n\n• TFM LIA MIGUEL ÁNGEL NÚÑEZ ESPINOSA.pdf (Master´s Thesis, containing a full description of the TSP)\n\nThese files are under restricted access due to the restrictions noted above. Access will be facilitated through the DANS website and approved by the corresponding author.\n\n\nF1000 Research Statement of Endorsement\n\nEva Samaniego Fernández confirms that the author has an appropriate level of expertise to conduct this research, and confirms that the submission is of an acceptable scientific standard. Eva Samaniego Fernández declares they have no competing interests. Affiliation: Universidad Nacional de Educación a Distancia.",
"appendix": "References\n\nHaigh A: The Council for Cultural Co-Operation. Landheer B, editors. Annuaire Européen/European Yearbook. Dordrecht: Springer; 1970. Publisher Full Text\n\nGreen R, Wall D: Language Testing in the Military: Problems, Politics and Progress. Lang. Test. 2005; 22(3): 379–398. Publisher Full Text\n\nJohnson RB, Christensen LB: Educational Research: Quantitative, Qualitative and Mixed Approaches. Boston, MA: Allyn and Bacon; 2004.\n\nRichards JC, Rodgers TS: Approaches and Methods in Language Teaching. New York: Cambridge University Press; 2001.\n\nNuñez Espinosa, Researcher M.A. Miguel A. (Miguel Angel Nuñez Espinosa): Training for NATO Level of English Language. DANS. 2019. Publisher Full Text\n\nAsher JJ: What is TPR?. TPR-World. 2012. 2012-05-29\n\nTrim J: The Work of the Council of Europe in the field of Modern Languages 1957 – 2001. Graz: Council of Europe; 2001.\n\nVan Ek JA: The Threshold Level. Council of Europe, Oxford, Pergamon Press; 1975.\n\n\nFootnotes\n\na https://www.natobilc.org/en/.\n\nb https://www.coe.int/en/web/common-european-framework-reference-languages/language-policy-in-the-council-of-europe.\n\nc See The Conference on Security and Cooperation in Europe (CSCE, 1992).\n\nd http://www.coe.int/lang-CEFR .\n\ne http://www.coe.int/lang-CEFR .\n\nf Albania, Germany, Belgium, Bulgaria, Canada, Czech Republic, Croatia, Denmark, United States, Estonia, Slovakia, Slovenia, Spain, France, Greece, Hungary, Iceland, Italy, Latvia, Lithuania, Luxembourg, Montenegro, Norway, Netherlands, Poland, Portugal, United Kingdom, Romania, and Turkey.\n\ng https://www.nato.int/cps/en/natolive/topics_52060.htm.\n\nh https://www.natobilc.org/en.\n\ni https://www.nato.int/cps/en/natohq/news_125041.htm.\n\nj https://www.nato.int/cps/en/natohq/news_125041.htm.\n\nk https://en.wikipedia.org/wiki/Military_ranks_of_Spain .\n\nl https://www.natobilc.org/en/.\n\nm https://www.natobilc.org/en/"
}
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[
{
"id": "240138",
"date": "08 Feb 2024",
"name": "Valentina Georgieva",
"expertise": [
"Reviewer Expertise military terminology",
"ESP",
"intercultural communication"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research work by Miguel Angel Nuñez Espinosa as the title suggests is attempted to suggest Training strategies for the improvement of NATO Level 2 results for English Functional Level exams in the armed forces. This title sounds very appealing to the community of Military English teachers and testers who devote efforts to support the English language learning of military professionals of NATO and PfP countries. Having worked in the Bulgarian military training system for 25 years and knowing in details the difficulties associated with a successful training and passing the STANAG 6001 Exam, I have expected practical guidelines for improving the training supported by statistical data. To my disappointment, however, the most important part – The Training Strategies Proposal – is not accessible without a special permission, which restricts the possible users to a limited number from the Spanish Armed Forces, I guess. Another proof of the locality rather than international applicability of the research is the author’s claim that “the TSP could help NATO L2 trainers and private academies to make changes and improvements” which hints to the fact that Spanish servicemen can be trained elsewhere which is not a rule in other countries (incl. Bulgaria), where English language training is done only at military institutions. One more drawback of the research is lack of the most important for the training process information, i.e. the number of classes. When the author writes 6 months and 1 year of training, it does not indicate the number of English language classes for this period. Thus, the text of the article, which is available publicly, does not provide sufficient details to allow replication by others. As a drawback, we can also note the rather outdated literature, which is referred to in the work. Probably the author does not follow the publications from the BILC conferences where the newest trends in military teaching and testing are discussed. The positives of the work should not be overlooked: firstly, the overall research design is very well thought of. Conducting research over an extended period requires good planning and consistency. Secondly, other practitioners who would like to receive feedback from their trainees could use the questions from this work for a similar survey. I would recommend the author to presents the results of his research in a more focused way. This could be done by elaborating on the practical aspects of the teaching the four language skills so that the desired NATO STANAG level is achieved. For example, the strategy “Breaking the ceiling” for developing speaking should be presented with examples of speaking questions or situations appropriate for level 1, level 2 and level 3 instead of the general comment that “Some questions that are relatively difficult are intentionally asked in order to find the upper limits of the examinee's ability.” In addition, the practical usability of the research for the teachers and testers of military professionals is not related to the CEF levels of proficiency and the equivalence of the CEF levels to STANAG 6001 levels (which is a very debatable topic), so this part is redundant. Overall, the research work is valuable for its attempts to reach conclusions based on sufficient data but the title does not meet the content in its publicly accessible form.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "235911",
"date": "19 Feb 2024",
"name": "Evgueniya Lyu",
"expertise": [
"Reviewer Expertise English language teaching and learning",
"ESP",
"course design"
],
"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\nWe would like to thank the author for the opportunity to review the manuscript. The paper attempts to describe a teaching program, Training Strategies Proposal (TSP), designed to address the language needs of NATO personnel. Given the crucial role of effective communication in international missions and joint operations, mastering a common language is paramount. To ensure that candidates achieve language proficiency corresponding to Level 2 (functional) or higher of the STANAG 6001 criteria, military personnel from NATO countries and those seeking career opportunities within the organization must take the STANAG 6001 exam. Hence, developing efficient teaching programs that prepare candidates for this exam appears to be of vital importance. Even though the article addresses urgent problems and tries to approach them from a needs-based perspective, a few concerns related to the research design and the validity of the results arise. Title The author might consider slightly changing the title of the article so that it conveys the research goal in more precise and concise terms. An example would be “Designing training strategies for the improvement of NATO level 2 English language proficiency exam results in the armed forces”. Keywords Reducing the number of keywords by leaving out the least relevant ones (such as, Independent Users exams, Functional exams, or combining others “Teaching English as a Second Language”, etc.) would contribute to the clarity of the purpose of the paper. Introduction The paper mentions “four skills – listening, speaking, reading, and writing.” First, it would have been more appropriate to refer to them as “four language skills.” Second, according to the CEFR, cited in the paper, “the traditional model of the four skills … has increasingly proved inadequate in capturing the complex reality of communication” (https://rm.coe.int/common-european-framework-of-reference-for-languages-learning-teaching/16809ea0d4, p. 33); instead, the document refers to general, linguistic, sociolinguistic and pragmatic competences, and it also extends the communicative language activities to include not only reception (oral and reading comprehension) and production (oral and written), but also interaction and mediation. In addition, the introduction lacks precision regarding “different techniques and newer methodologies” and the results obtained. Overall, the introductory section of the article is too short. At least it should provide an account of the methodology that will be used to address the research question. Literature review There seems to be a confusion as to the very essence of literature review. This section is usually used to provide theoretical grounds for the work, which is not the case here. Instead of presenting an overview and analysis of the existing scholarly literature about the research topic, the author provides a detailed and somewhat unnecessary description of the existing language proficiency standards. As the main purpose of this section is to compare two language scales (CEFR and STANAG 6001), the author might consider using a different subheading. Also, the abbreviation commonly used to refer to the Common European Framework of Reference for Languages is CEFR and not ‘CEF’ as it appears in the article. Moreover, one cannot but wonder why Table 1 contains information on the scales that are not detailed in the section (Campaign, ALTE, Cambridge ESOL). Another element worth examining is the notion of language mistakes. Indeed, the paper states that “[t]he need for linguistic communication was particularly important in order to avoid any misunderstanding because of the risk in case of language mistakes.” So, the reader may presume that language mistakes impact understanding. However, a distinction should be made between errors and mistakes: whereas errors, i.e., “incomplete knowledge” or “incomplete learning” ([11], p. 201), may prevent successful communication, mistakes are viewed as performance flaws due to, for example, inattention or fatigue ([12], p. 599). Therefore, it would have been more exact to use the term “errors” in the context of the article. Methods Study design The section would benefit from a more detailed specification of the content of the NATO L2 training and the TSP as well as the content differences between the 6-month and 1-year programs. The author mentions “a mixture of methods and approaches, including audiolingual method, direct method and physical response method” [10]. However, the reference, even though seminal, seems somewhat outdated. An exploration of why these methods were chosen over more contemporary approaches, like communicative, competency-based, content-based, or task-based methods, would enrich the discussion. In addition, the paper indicates that a “mix of methods was done in order to meet the different needs of the examinees.” The question arises as to how the needs of the examinees were determined. The article would gain in coherence if the different “studies” were presented as the four different phases of the same study. All the more so as these were designed to address the same research goal. Participants Given the information concerning the study participants, it would have been appropriate to use the term “convenience sampling” (for more information,[5], [7]). While the paper provides insightful details about the military categories to which the participants belonged, further exploration of how this variable intersects with the participants’ needs, motivation, and exam results would add depth. Additionally, the mention of “psychological instruments” raises questions that could be addressed, offering a more comprehensive understanding of the study’s methodology. Finally, when it comes to the number of participants, at this stage the reader might wonder why only 40 out of 50 participants took part in the TSP. A brief explanation in this section would contribute to the overall clarity of the research design. Study 1: In this subsection, the author notes that “[f]ive of the questions were open-ended questions that ask the examinees to provide their opinion.” However, the specific nature of the opinion sought from the participants remains somewhat unclear. Furthermore, the paper refers to the questionnaire as a “scale and rate”: in the literature on research design, such questionnaires are typically referred to as Likert scales [7], and it is often recommended that research designers include an even number of responses in Likert scales to avoid neutral answers, which can pose challenges in interpretation. Study 2 Training Strategy Proposal (TSP) The opening of this subsection appears to feature overgeneralized descriptions that lack specific details in terms of both the theoretical framework (“books and essays”) which served as a basis for the research design and more specifically, the ways in which the TSP was conceived (“elements, materials, and procedures”). To enhance this section, the author might consider addressing the following questions:\nHow was the training personalized? What is the most effective approach to integrating the four language skills? In what specific ways were these skills addressed?\nQuestionnaire The subsection would have been enhanced by a detailed description of the questionnaire design. Designing questionnaires is a complex process that requires careful consideration of various factors to ensure the validity and reliability of results [6],[7],[4]. Therefore, one might question the rationale behind selecting specific items for the questionnaire. Another aspect deserving more detailed exploration is the concept of motivation. The questionnaire includes only two questions (items 1 and 3, Box 1) on motivation. Motivation is widely recognized as a central notion in any learning-related context [2], [3], [9]; motivation can be extrinsic and intrinsic; it can be explicitly measured through questionnaires and observation, and it can also be measured implicitly through questions that seem to have no apparent link with motivation (Do you think time passes faster while studying English? ([4], p. 144). Finally, it remains unclear whether the questionnaires were administered in English or in Spanish, and whether the participants were required to answer open-ended questions in English or in Spanish. Concerning the description of the TSP, a few elements pose problems. First and foremost, it would have been useful to provide a brief account of the proposed names for the training of each skill (i.e., “Listening fatigue stairs”, “Breaking the ceiling”, etc.). Second, providing concrete examples of the teaching tasks used in the training would enhance the article’s clarity. Even though the article indicates that “[a]dditional information about what the TSP contained can be found in the Extended data,” we were unable to access these supplementary documents. Third, introducing the concept of “fatigue” in listening comprehension tasks would benefit from references to scientific literature on the topic. Moreover, integrating the concept of “cognitive load” could significantly enrich the discussion ([1], p 56-89). Next, the section on the speaking part of the program lacks an explanation of the tasks used to develop speaking skills. Furthermore, the information concerning reading tasks requires more precision, for instance, concerning the length of “a piece of text” and a book. Was the content of the reading tasks specialized (i.e., military-related)? The author uses subjective wording “anything enjoyable”: exploring this idea from a motivational perspective could be beneficial. We might suggest the author delve into the literature on specialized fictional narrative, particularly prolific in France [8]. Also, the author might consider referring to the participants as “learners” rather than “students”. The article mentions “multiple strategies (memory, cognitive, compensation, metacognitive, affective, social and test-taking).” While one might presume the reference to Oxford’s learning strategies (1990), the inclusion of the test-taking strategy raises curiosity about its origin. Additionally, it would be interesting to explore whether all these strategies are equally relevant to reading tasks. More generally, understanding the author’s position regarding specialized content and its potential role in student motivation would contribute to a more comprehensive understanding of the program. Results The general comment regarding the results section is that the data are statistically insignificant for drawing any conclusions or generalizing the results. Study 1 The paper mentions that the participants valued interaction and criticized the monotonous and redundant nature of traditional programs. It can be inferred that this information comes from the interviews with the participants, as no questionnaire items cover these elements. Nevertheless, a more explicit reference to the participants’ answers would be a welcome addition. The paper states that “[t]he majority of the participants weren’t confident with the English language and weren’t satisfied with the training, trainers, and the organization of the course” (Q2 (open-ended) & Q15, Q6, Q7, Q11). According to the information provided in Table 2, 13 participants expected to pass L2, contrary to 3 participants who did not (the other answers to this question remain comparable); the results appear to be comparable regarding the participants’ satisfaction with the training and the trainers. Moreover, the participants were rather satisfied with the organization of the training. In addition, the section lacks information concerning interview answers. Study 2 Representing the numbers in percentages could provide an easier comparison of the results. Study 3 Representing the numbers in percentages could provide an easier comparison of the results. Concerning the interpretation of the results, the data are statistically insufficient to draw any conclusions. Moreover, other factors, such as previous exposure to the exam modalities and language habits, might have interfered with the results. Study 4 A few conclusions require a more thorough analysis. For instance, the statement “some examinees felt again that they needed longer courses with fewer students” (Q13 & Q14) appears to have been misinterpreted, particularly regarding the number of students per group. The conclusion “[i]t is particularly noteworthy that almost all of them felt that the TSP training program was motivational and interesting” requires supporting evidence. The author might also consider presenting the results from Study 1 and Study 4 in one table for easier comparison. Based on the idea that more efficient training is needed for NATO personnel to pass the L2 exam, the author designed the TSP training proposal and attempted to test its effectiveness through the examination of the questionnaire results and the success rate at the L2 exam. While this is a valid initiative, it is premature to affirm the actual effectiveness and efficiency of the training. To draw such conclusions, more participants should be involved in the study, and a more elaborate questionnaire should be employed. Furthermore, the author might explore additional methods to evaluate the efficiency of the training program, such as assessing students’ performance on various tasks and observation. Another aspect worth exploring to eliminate potential biases is providing more information about the trainers’ profiles. Consider the following questions:\nHow many trainers were involved in the program? Was the author the only trainer? Were the trainers informed about the objectives of the program and the ongoing study? Did they receive any guidelines concerning the teaching program? Were they instructed to provide feedback?\nReflecting on these questions could help reduce significant biases in the research. If the trainers had been sensitized to the issues at stake, their teaching methods might have influenced the final survey results. Discussion The section “Summary of the study results” is redundant and can be omitted. Other comments Our final remark pertains to the language and style of the paper. We strongly recommend that the author thoroughly proofread the text to eliminate serious grammatical and vocabulary mistakes, improve sentence structure and punctuation (including the format of apostrophes and quotation marks) and achieve spelling coherence (AmE vs BrE). One element to consider is the keyword “English for a Specified Purpose”: the traditionally accepted term is English for Specific Purposes. The inaccurate use of some words and expressions in the text hinders the overall comprehension of the article. Some sentences and paragraphs need to be completely rephrased to avoid unclear and ambiguous statements. For instance, the abstract reads “one of the main tasks of the NATO multinational setting [emphasis added] is the teaching and the assessment of languages”, as if the “multinational setting” is a special representative body of NATO with specific tasks. Another example of this can be found in the following statement: “If the examinees do not achieve those levels […], NATO members can be affected by a reduction of financial support or the assignment to NATO postings.” [emphasis added] A further example of this is the use of the expression “NATO countries”. It would have been more appropriate to write “NATO member countries” or “NATO Allies”. Another major flaw of the article is its lack of transitions between sections, which renders the reading particularly difficult. The reading would have been more pleasant if the text had included introductory and concluding paragraphs at the beginning and at the end of each section respectively.\n\nReferences When it comes to referencing, three major issues can be brought out. Firstly, the references do not comply with the standard reference formats. For instance, they do not appear in the alphabetical order, there is no mention of the date on which the online resources were accessed, and some quotations lack page numbers, e.g. Green & Wall (2005) “some teams have taken a general English approach in their testing, others have incorporated a military flavour,‟ and still others have used texts taken from military sources and tasks based on military scenarios”. This example further illustrates the recurrent punctuation issues in the text. Also, the author offers no explanation for the distinction made between the footnotes and endnotes. The referencing would have been clearer if the author had considered presenting all the references in the end under the section ‘References’. Secondly, some quotes miss reference to the source document. Finally, the “References” section at the end of the article fails to include some key documents such as the STANAG 6001 with a detailed description of the Language Proficiency Levels.\n\nIn conclusion, the present paper can be considered a pilot study that potentially paves the way for a more robust research design and data analysis.\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?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "240134",
"date": "21 Feb 2024",
"name": "Frane Malenica",
"expertise": [
"Reviewer Expertise Morphology",
"syntax",
"corpus linguistics",
"experimental linguistics"
],
"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 generally interesting piece of research with clear aims and goals and a well-defined methodology. The author does a very good job contextualizing the importance of the research in the \"bigger\" picture perspective, collected a sufficient amount of relevant data and drew valid conclusion from the data. The only suggestion/issue that I have with the paper is that an inferential statistics test (e.g. a paired samples t-test) could have been used to examine whether there is a difference between pre- and post-training results, as I believe that would have given the results more validity.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1304
|
https://f1000research.com/articles/10-1302/v1
|
22 Dec 21
|
{
"type": "Research Article",
"title": "Senior Citizen Activity Centre E-commerce and Cybersecurity: The Way Ahead to IR 4.0",
"authors": [
"Swee Leng Tan",
"Rossanne Gale Vergara",
"Nasreen Khan",
"Shereen Khan",
"Rossanne Gale Vergara",
"Nasreen Khan",
"Shereen Khan"
],
"abstract": "Background - The Malaysian ageing community’s IT aptitude is limited and is a key factor preventing Malaysia’s ageing population from successfully entering Industry 4.0. This study aims to digitalize Malaysian older people with e-commerce. This will require cybersecurity awareness training due to potential cybersecurity threats when conducting business online.\n\nFurthermore, this study advances the Industry 4.0 initiatives set by Malaysia’s National Industry 4.0 Policy Framework by means of a voluntary community-based training program. It also creates a policy that elevates Malaysia’s senior citizens’ current level of ICT innovation baseline commensurate with Industry 4.0 transformation standards. Methods – Participatory action research was conducted with members in a Senior Citizen Activity Centre (PAWE) through focus group discussions. Each focus group consisted of 6-8 people. Through identifying the community’s problem in the focus groups, an e-commerce platform was developed for the elderly to commercialise their existing products. The dissemination of e-commerce training and cybersecurity awareness were also conducted as part of mitigating fraud relating to online transactions.\n\nResults – The findings show that PAWE members’ IT aptitude was limited, that they needed assistance with understanding the e-commerce platform, and that they had limited cybersecurity awareness.\n\nConclusions – The country’s ageing population programs and services are preparing for an ageing nation. In order for Malaysia’s ageing population to become self-sustainable, researchers suggest that Malaysian older persons become entrepreneurs. Third generation entrepreneurs must also be supported by social innovation, technological innovation, and cybersecurity awareness, which leads to achieving IR 4.0 and meets the economic, social and sustainable environmental goals.",
"keywords": [
"Ageing population",
"Cybersecurity",
"Entrepreneurship",
"Industry 4.0"
],
"content": "Introduction\n\nMalaysia will reach an ageing nation status by 2030. This means that more than 14% of the population will be 60 years of age or older (Department of Statistics Malaysia, 2021). The Malaysian government reported that in 2020, “there are 3.7 million senior citizens in the country, and it is expected to increase by 15.3%, to 5.3 million senior citizens in 2030” (New Straits Times, 2021). Malaysia has less than nine years as of writing this article to ensure the infrastructure, programs, and services for the ageing population are ready. Under the Ministry of Women, Family and Community Development’s (KPWKM) Department of Social Welfare (JKM), with other government agencies and non-governmental organizations (NGOs), Malaysia currently has 148 Senior Citizen Activity Centres/ Pusat Aktiviti Warga Emas (PAWE). These centres were developed for senior citizens to carry out daily activities in the community. Joining PAWE is free of charge to Malaysians and activities include but are not limited to: religious, recreational, therapy and rehabilitation, health seminars, and training courses. To alleviate the burden on the government, this study explored a self-sustainable solution for PAWE, which includes social innovation, technological innovation, and cybersecurity awareness to achieve Industry 4.0.\n\nIndustry 4.0 (IR 4.0) refers to the fourth phase of the Industrial Revolution. In IR 4.0, cyber-physical systems are emphasised, and focusing on interconnectivity, automation, and machine learning. However, while social media and the internet are vital to daily life, this is the extent of Malaysian senior citizens’ IT aptitude in PAWE. This limitation in PAWE member’s technology use and technical know-how are key factors preventing older Malaysians from successfully entering Industry 4.0, which is contrary to the Malaysian government’s initiatives as stated in the National Industry 4.0 Policy Framework. Furthermore, while the country currently has Cybersecurity laws, awareness of cybersecurity and cyber resilience among the Malaysian ageing population is also limited. Cybersecurity is another key element in the IR 4.0 transformation, which is to ensure information systems and manufacturing lines are protected from ubiquitous cybercrime threats.\n\nThis study aims to identify the challenges preventing the Malaysian ageing population, specifically members of Senior Citizen Activity Centres (PAWE), from reaching Industry 4.0. Once the problem is identified, PAWE members together with the researchers can solve the problem and develop a sustainable solution for PAWE to advance to the IR 4.0 set by Malaysia’s National Industry 4.0 Policy Framework. Lastly, this study aims to create a policy that proposes a self-sustainable solution for Malaysia’s ageing population with minimal financial assistance from the government.\n\nIndustry 4.0 is associated with rapid technological advancements that lead to transformations in the socio-economy. Luppicini (2012) talks about whether the fast growth in technological development and digitization is leaving a positive influence on individuals and society. Rifkin (2014) strongly calls for further research to address the various unexpected consequences of the rapid pace of technological developments. One of the most important challenges faced by governments, policy makers, and society is also how to tackle the set of technology disruptions associated with this new industrial era (McKinsey, 2016; Zervoudi, 2020). Industry 4.0 is fast approaching Malaysia and the Malaysian government is preparing the nation according to the National Industry 4.0 Policy Framework. While social media and internet use has become a part of the everyday lives of older Malaysians, that is the extent of the older population’s IT aptitude. The ageing population in Malaysia is rich with experience, property, and human networks; however, their current level of technology knowledge has not reached the Industry 4.0 level. As such, this study of the Malaysian ageing population, specifically from PAWE, explores the gaps that prevent them from achieving Industry 4.0.\n\n1. What are the challenges preventing Malaysia’s senior citizens in PAWE from achieving Industry 4.0?\n\n2. How can Malaysia’s entrepreneurs in PAWE become self-sustainable in Industry 4.0?\n\n3. How does social innovation help achieve industry 4.0 for Malaysia’s ageing population?\n\n\nMethods\n\nThis study was conducted using a Participatory Action Research (PAR) approach to address the Malaysian third age entrepreneur limitation in digitalization and determine how best to disseminate the solution for them to prepare for Industry 4.0. Action research is an iterative process and does not end until the problem is solved. PAR studies with older people is limited in that there is a power difference between the older person and researchers (Corrado et al., 2020). However, in this study, the PAWE members were active partners in the problem solving and solution implementation.\n\nData was collected in March to April 2021. Participants were selected by purposive sampling from direction by Malaysia’s Department of Social Welfare (JKM). Participants were all above the age of 60 men and women in Senior Citizen Activity Centre (PAWE) Sepang, Malaysia.\n\nData was collected through face-to-face focus group discussions led by the corresponding author, a PhD holder in gender and socio-legal studies. Data was also collected through observations and field note taking. The focus group consisted of 6 people and lasted for one hour. Questions asked during the focus group were:\n\n1. How are you currently running your business?\n\n2. Who are your customers?\n\n3. How do you receive your orders or reservations?\n\n4. Are you comfortable using technology to run your business?\n\n5. What do you know about cybersecurity?\n\n6. Do you know how to protect your data?\n\nThe first phase of PAR required ‘diagnosing’ the problem of concern for the PAWE community, as seen in Figure 1. In this phase, the PAWE members conveyed their concerns for not knowing how to sell their handcrafted goods and services in an online platform. Once identified, the next phase ‘action planning’ required the participants and researchers to devise a solution to the problem. In this phase, the researchers and PAWE members agreed that a website was necessary for them to sell their products.\n\nHowever, hands on training and cybersecurity training were a necessary part of ensuring the PAWE members understood the how to use the website and safely use the e-commerce platform. The next phase ‘taking action’ required implementing the proposed solution. According to the Organisation for Economic Cooperation and Development (OECD), social innovation is “the design and implementation of new solutions that imply conceptual, process, product, or organisational change, which ultimately aim to improve the well being of individuals and communities.” For the purpose of this study, social innovation facilitated as part of the solution to PAWE’s difficulty in connecting small business products to an online platform. In this case, a website tied to an e-commerce platform and social media to help the PAWE community sell their products online was developed by a private Malaysian IT services company. The dissemination of e-commerce training and cybersecurity awareness was also conducted as part of the mitigation to prevent online fraud relating to online transactions. Following this phase, ‘evaluating’ the solution implemented was observed. The last phase ‘specify learning’ was to identify general findings.\n\nResults of the discussions from field notes were transferred to an excel sheet for participants to verify and from there, themes were determined manually. Themes such as “traditional” were determined from the focus group discussions. “Not comfortable” or “Not knowledgeable” and “Need assistance” regarding technology and cybersecurity was a common theme among the PAWE members.\n\n\nResults\n\nThe results of the focus group discussions show that PAWE members did not have the experience to conduct e-commerce on their own. The participants in the study owned and operated smart phones. However, they requested that their children or younger person in PAWE assist them for anything technical. Their use of technology was limited to using social media in their smart phones and its basic features i.e. messaging, watching and downloading videos and files. The participants pursued entrepreneurship in a traditional way. They sold their handmade products or services face-to-face. When asked to use an e-commerce platform such as Amazon, Shopee or Lazada, they were not certain how to do it and were overwhelmed by the idea of creating a website for their community. Once the researchers clarified that the PAWE members were not expected to create their own website and that a private company was engaged to develop a website as a social innovation product, the PAWE members were relieved and were more accepting of the idea of using an online platform connected to their social media apps. The participants during the first phase of diagnosing the problem mentioned they will ask their children to help them with technical issues regarding the e-commerce platform. The researchers engaged a private Malaysian IT services company as part of the ‘taking action’ phase to develop a website as a social innovation product for the PAWE community to sell their products/services online. The website linked purchases to the PAWE community’s social media to help track and fulfil orders, since the community is well versed on using social media apps such as WhatsApp and Facebook. As part of implementing the solution, training on cybersecurity awareness, cybersecurity threats while using social media and e-commerce were also conducted.\n\nAs observed in the first phase of the PAR study, the PAWE members were ready to give the responsibility of handling the website and administrative duties to the younger member assigned to the centre. The IT company and researchers trained this representative and all six of the main PAWE members in the focus group on how the website works and key features for the IT administrator.\n\nDue to the COVID-19 pandemic, a web-based solution to assist PAWE members sell their products/services is ideal. Malaysia is still limiting the opening of the economy and online businesses are often sought after in the new normal.\n\n\nDiscussion\n\nThe participants for this study have previously used traditional methods in selling their products/services such as face-to-face retail services i.e., food and beverage, hospitality, health and wellness, and handicrafts. Moving their business to an online e-commerce platform was novel for them and a challenge to the participants due to their limited technical knowledge and know how. Although, they had traditional views on selling their products initially, they were open to learning more about the e-commerce platform the researchers proposed for them to use. The participants were also open to learning more about cybersecurity, since they were planning to move their business to the e-commerce platform. This is a step forward for the PAWE participants in achieving IR 4.0 and becoming more self-sustainable entrepreneurs in the digital age. The results of this study are contrary to previous results such as Corrado et al. (2020), which showed that older persons “are rarely positioned as equitable partners, co-learners, or agents for change” in PAR. In the case of our study however, the PAWE senior citizens were motivated to adopt a technology, provided that they have a younger person close to them to assist with the technical aspects of the project. The PAWE members’ interest in expanding their business by moving it to an online platform was positive. Although, while some of the PAWE members showed interest in using the online platform themselves, it was for the benefit of their own business and separate from the proposed one-stop-shop platform for the entire PAWE community.\n\n\nConclusions\n\nThe Malaysian government is preparing well before it reaches ageing nation status in 2030. The current government’s programs and services are in line with this goal of preparing the nation. However, in order for the senior citizens in PAWE to become self-reliant and self-sustainable, the researchers suggest that PAWE continue to stay active in learning about new technologies to support their small businesses, which is supported by social innovations, technological innovation and cybersecurity awareness. This leads to healthy ageing and achieving IR 4.0 whereby the Malaysian senior citizens meet the economic, social, and sustainable environment goals.\n\nThe study shows that PAWE has active entrepreneurs. However, the technology innovation aspect was previously not there. Their IT aptitude was limited to using basic smart phone functions and social media. Combining Technological Innovation, Social Innovation and Cybersecurity Awareness helps improve the senior citizen entrepreneurs in PAWE to reach IR 4.0 as seen in this study.\n\nThe PAWE members were introduced to an e-commerce platform to advance their business digitally. Although some of the members were reluctant at first, they embraced the technology with the assistance of their children. An inter-generational factor is significant and should be explored in future studies, since the younger generations can assist senior citizens having IT technical issues.\n\n\nEthical approval\n\nEthical Approval was granted by the Research Ethics Committee of Multimedia University (approval number EA0312021).\n\n\nParticipant consent\n\nConsent was obtained from all participants written (signed) and verbally.\n\n\nData availability\n\nFigshare: Focus Group Discussion Results PAWE. https://doi.org/10.6084/m9.figshare.16531071.v1. Tan Swee Leng et al. (2021a)\n\nFigshare: COREQ for PAWE Ecommerce Cybersecurity\n\nhttps://doi.org/10.6084/m9.figshare.17135117.v2. Tan Swee Leng et al. (2021b)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Author contributions\n\n\n\nTan O: Conceptualization, Data Curation, Funding Acquisition, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing; Vergara R: Formal Analysis, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing; Khan S: Writing – Review & Editing; Khan N: Formal Analysis, Writing – Review & Editing\n\n\nAcknowledgments\n\nThe authors wish to thank the members of Senior Citizen Activity Centre/ Pusat Aktivity Warga Emas (PAWE) for participating in this research. They were actively involved throughout the study, providing invaluable data and recommendations to improve the recommended solution.\n\n\nReferences\n\nCorrado AM, Benjamin-Thomas TE, McGrath C, et al.: Participatory Action Research With Older Adults: A Critical Interpretive Synthesis. Gerontologist. 2020; 60(5): e413–e427. PubMed Abstract | Publisher Full Text\n\nDepartment of Statistics Malaysia: Population and Demography. 2021. Reference Source\n\nLuppicini R: Ethical Impact of Technological Advancements and Applications in Society. IGI Global. 2012. Publisher Full Text\n\nMcKinsey I: Industry 4.0 after the initial hype: Where manufacturers are finding value and how they can best capture it. McKinsey Digital. 2016. Reference Source\n\nNew Straits Times: Rina: Malaysia prepares for ageing nation status by 2030. New Straits Times. 2021. Reference Source\n\nRifkin J: The Zero Marginal Cost Society: The Internet of Things, the Collaborative Commons, and the Eclipse of Capitalism. St. Martin's Publishing Group. 2014. Reference Source\n\nSusman G: Action Research: A Sociotechnical Systems Perspective. Ed. G. Morgan. London: Sage Publications, 1983; 95–113. Reference Source\n\nTan Swee Leng O, Vergara RG, Khan N, et al.: Focus Group Discussion Results PAWE. figshare. Dataset. 2021a. http://www.doi.org/10.6084/m9.figshare.16531071.v1\n\nTan Swee Leng O, Vergara RG, Khan N, et al.: F1000-COREQ_checklist PAWE ECOMMERCE CYBERSECURITY.pdf. figshare. Figure. 2021b. http://www.doi.org/10.6084/m9.figshare.17135117.v2\n\nZervoudi E: Fourth Industrial Revolution: Opportunities, Challenges, and Proposed Policies, Industrial Robotics - New Paradigms, Antoni Grau and Zhuping Wang, IntechOpen. 2020. Publisher Full Text"
}
|
[
{
"id": "135920",
"date": "30 May 2022",
"name": "Salawati Mat Basir",
"expertise": [
"Reviewer Expertise International development law"
],
"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 is very interesting and touches on a topic that is very rare for people wanted to discuss. The authors show the importance of the ICT to all the senior citizens but at the same time remind the reader about the issue of cyber security.\nThe data collection and the questions asked to the participants are really connected to the main topic.\nFrankly, this article is excellent and important to discuss how the PAWE activities regarding e-commerce and, the threat of cybersecurity that the senior citizens do not understand. The introduction by the authors clearly stated the percentage of senior citizens in Malaysia and the number of PAWE under the Ministry of Women, Family and Community Development, other government agencies and NGOs. The authors address a very important issue in their problem statement regarding the National Industry 4.0 Policy Network that many ageing populations especially at the PAWE not compatible with the current technology and are yet to reach the 4.0 level. This article also uses Participatory Action Research (PAR) approach for their methodology to address the issue where their results are much more accurate to understand the level of technology among the senior citizen at PAWE despite only PAWE in Sepang, Selangor was selected for sampling.\nThe result of the approach by the authors successfully shows that the participants previously using the traditional method in selling their products and services and the changing platform to online commerce really a challenge for the participants due to their limited knowledge and practice of online commerce.\nThe authors also successfully proved that PAWE has active participants in the e-commerce business and come out with the suggestion for government to expand more assistance for the participants even though the younger generations in the family of senior citizens actually help them a lot.\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": "158427",
"date": "06 Feb 2023",
"name": "Nai Peng Tey",
"expertise": [
"Reviewer Expertise Demography and population stjudies"
],
"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 \"Senior Citizen Activity Centre E-commerce and Cybersecurity: The Way Ahead to IR 4.0\" deals with the use of technology among older adults in conducting their businesses. It is a good exploratory study on this topic, to stimulate more large scale research for policy formulation.\n1. General comments:\nInappropriate use of words or terms\n\n\"IT aptitude\" -it should be IT skill or knowledge\n\n\"Malaysian older people\", \"Malaysian ageing population\" - rewrite as 'older Malaysians'\n\n\"To commercialize their existing products\" - change 'to sell and buy things'\n\n\"Senior citizen\" - 'older adults' is a more appropriate term\n2. Abstracts:\nThe Background in the abstract must be reorganized, starting with problem statement, followed by the objectives of the study.\n\nThe objectives must be reworded. A single study such as this cannot aim to digitize Malaysian older people, nor can it advances the Industry 4.0 initiatives set by Malaysia’s National Industry 4.0 Policy Framework by means of a voluntary community- based training program. it can only aim to provide a better understanding on the involvement of older Malaysians in e-commerce\n3. Introduction\nIn the introduction - the study cannot create a policy - it aims to provide some inputs to inform policy.\n\n\"However... this is the extent of Malaysian senior citizens’ IT aptitude in PAWE\"- This sentence is not clear.\n\nI suggest you combine this with the next sentence: While social media and the internet are vital to daily life, older Malaysians, including PAWE's members limited technology use and technical know-how prevented them from successfully entering Industry 4.0, as envisaged under National Industry 4.0 Policy Framework.\n4. Objectives\n\"Lastly, this study aims to create a policy that proposes a self-sustainable solution for Malaysia’s ageing population with minimal financial assistance from the government\" - This study cannot possibly create a policy - at best if can provide an input or create some awareness to the policymakers.\n5. Participant selection\n\"Data was collected in March to April 2021. Participants were selected by purposive sampling from direction by Malaysia’s Department of Social Welfare (JKM)\" - it is more appropriate to state 'in consultation with the Department of Social Welfare', instead of being directed.\n6. Data collection\n\"Data was collected through face-to-face focus group discussions\" (in March and April 2021)… The authors did not state how many FGDs (face-to-face group discussions) were conducted. They merely stated six participants per group. Since the field work was conducted over March and April, I would assume that there would be more than one FGD. Moreover, the paper did not state where the participants came from. The goods that they buy and sell are also not clearly stated. E-commerce deals with both buying and selling. If they all come from one locality and selling only handicrafts, the study cannot claim to be representative of the country.\n7. Results\n\nFrom the results section, it appears that there is only one FDG, and the time taken was for follow-up action.\n\nPerhaps a more detailed description of the participants is warranted - the age, sex, ethnicity, locality, years in business, types of goods and services traded (buying and selling).\n\nThe statement \"since the community is well versed on using social media apps such as WhatsApp and Facebook\" contradicts the earlier claim that PAWE's members have limited technical knowledge and knowhow.\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/10-1302
|
https://f1000research.com/articles/10-1300/v1
|
21 Dec 21
|
{
"type": "Brief Report",
"title": "Potential use of absorbance scanning in differentiating tumor microenvironment compositions from endoscopic biopsy of colorectal cancer patients.",
"authors": [
"Murdani Abdullah",
"Amanda Pitarini Utari",
"Saskia Aziza Nursyirwan",
"Dimas R. Noor",
"Amanda Pitarini Utari",
"Saskia Aziza Nursyirwan",
"Dimas R. Noor"
],
"abstract": "Background: The microtumor environment is an area where tumor cells are surrounded by several cells such as immune cells, stromal cells and endothelial cells as well as blood and lymphatic vessels. It is known that various cytokines and growth factors are released by various cells surrounding the tumor and affect the growth of tumor cells. Differences in chemical composition in the microtumor environment can be detected using spectrometry. The aim of this study was to examine the potential of scanning absorbance spectrometry in differentiating cells based on the chemical composition of endoscopic biopsies of colorectal cancer patients. Methods: An endoscopic biopsy of the patient from Cipto Mangunkusumo Hospital, Jakarta was collected and homogenized in phosphate buffer saline using TissueLyser. Scanning absorbance was performed using a UV-VIS spectrophotometer. The results of scanning absorbance were then processed using principal component analysis (PCA) in Orange Data-Mining version 3.28.0 software and the results were represented in a scatter plot diagram. Results: Based on the results of the analysis using PCA, three patients were identified in different quadrant regions, crc006 and crc011 obtained from patients with the differentiation status located close together while crc009 and undifferentiated were located far apart. Conclusion: This indicates the potential of scanning absorbance in differentiating the chemical composition of the tumor microenvironment from patient biopsies.",
"keywords": [
"absorbance scanning",
"tumor microenvironment",
"compositions",
"endoscopic biopsy",
"colorectal cancer"
],
"content": "Introduction\n\nThe tumor microenvironment is an area surrounding a tumor consisting of various cells including stromal cells (Wang et al., 2017), immune cells (Winkler et al., 2020), endothelial cells, blood, and lymph vessels (Wei et al., 2020). The intra-tumoral composition of the tumor microenvironment can influence the tumor progression (Whiteside, 2008) and the clinical outcome of patients. To be able to determine the intra-tumoural composition, one common method is histopathological evaluation of the patient's biopsy (Schillaci et al., 2019). However, the biochemical composition of the biopsy such as metabolites and cytokines requires further tests such as immunohistochemistry of cell markers. (Oudijk et al., 2015) On the other hand, tumor progression may be influenced by chemical compositions within the tumor microenvironment such as cytokines and growth factors (Landskron et al., 2014; Yuan et al., 2016).\n\nOne of the simple methods that can be used to distinguish chemical compositions is spectrometry and potential differences of chemical compositions in malignancy such as changes in amino acid concentrations (Balan et al., 2019). Previously, Nogueira et al., (2021) showed that a tumor can be detected using diffuse reflectance spectroscopy in colorectal cancer diagnosis. Another study by Yang et al., (2016) showed the potentiality of visible-absorption spectroscopy as a biomarker to predict treatment and prognosis of esophageal cancer. In this study, we report absorbance scanning to distinguish three biopsies from three different patients. The absorbance scanning was carried out at a wavelength of 400–1000 nm using a spectrophotometer followed by Principal Component Analysis Orange Data Mining.\n\n\nMethods\n\nAll subjects gave their written informed consent for inclusion before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of the Faculty of Medicine, Universitas Indonesia (Protocol ID: 20-04-0643, version 02, June 29th, 2020). The tissue samples taken from an endoscopic biopsy from patients from Cipto Mangunkusumo Hospital, Jakarta were confirmed as cancer by an anatomic pathologist in the Department of Pathological Anatomy, Faculty of Medicine, Universitas Indonesia. They were then put into transport media in phosphate buffer saline (PBS) and transferred to the laboratory of the Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia in less than two hours.\n\nThe samples were minced into smaller tissue fragments, transferred to 1.5 ml centrifuge tubes, and homogenized by TissueLyser II (Qiagen, Germany) for 10 minutes. The suspensions were diluted in PBS to 1 mL.\n\nThe samples underwent wavelength scanning at λ = 400–1000 nm using the Agilent Cary 60 UV-Vis spectrophotometer (Agilent, Unites States). The absorption spectrum of the lysate cell was examined and feature selection was carried out using principal component analysis (PCA) to simplify the wavelength dimensions into principal component (PC) features that were not correlated (Abdullah et al., 2021). The resulting PC features were then used to classify the cancer patient samples into a scatterplot. The absorption/absorption spectrum pre-processing and PCA analysis were performed using Orange Data-Mining version 3.28.0 (Orange Data Mining, RRID: SCR_019811) (Demšar et al., 2013).\n\n\nResults\n\nIn this study, we recruited three different patients namely CRC006, CRC009, and CRC011. In the samples collected from patients, CRC006 and CRC011 similar clinical characteristics such as histopathology results were observed. Welldifferentiated rectal adenocarcinoma with metastatic sites were found in both patients. The sample collected from patient CRC009 had different clinical characteristics compared to CRC006 and CRC011, and CRC009 was found to have undifferentiated adenocarcinoma without metastasis. Sample data are shown in Table 1. (Abdullah et al., 2021)\n\nFigure 1 shows that each cell produces an absorption spectrum fingerprint in the wavelength range of 400–1000 nm. Just by observing the form of the absorption/absorption spectrum, it can be seen at first glance that fingerprints were only contributed to by the concentration of the molecule. To investigate the characteristic features of the spectrum, a principal component analysis (PCA) was carried out, which resulted in PC1 as the main feature (Abdullah et al., 2021). The results of the scatterplot with PC1 and PC2 showed that the sample CRC011 was well grouped in quadrant 1, CRC006 in quadrant 4, while CRC009 was spread between quadrants 2 and 3. From Figure 1 it can also be seen that each type of sample group appears to experience separation/classification when compared to other groups.\n\nCRC: sample number.\n\n\nDiscussion\n\nThe light absorption spectrum is known as a “molecular fingerprint” which allows the analysis of molecular types and their amounts/concentrations. In Table 1, we show three representative colorectal cancer biopsies collected endoscopically from patients: CRC006 was a patient with welldifferentiated rectal adenocarcinoma with metastasis, CRC009 was from a patient with undifferentiated adenocarcinoma, CRC011 was from a patient with welldifferentiated adenocarcinoma with metastasis. Interestingly, based on the PCA analysis of the absorption spectrum of the lysate sample (shown in Figure 2), the CRC006 quadrant was closer to CRC011, which has similar clinical features of welldifferentiated adenocarcinoma and metastasis. On the other hand, CRC009 with undifferentiated and located far from CRC006 and CRC011 respectively, which indicated their closer chemical composition. Such existence of grouping indicates that there were differences in cellular composition between the three samples; although further studies with a larger number of samples are needed to further confirm the clustering that occurs.\n\nIn biological tissue samples, several molecules contribute to the absorption spectrum in the ultraviolet (UV) to nearinfrared (NIR) regions. Protein and DNA absorb in the UV region, whereas tryptophan, NAD+ (nicotinamide adenine dinucleotide), collagen, elastin, NADH, and FAD (flavin adenine dinucleotide) are important endogenous chromophores in biological tissue (Yang et al., 2016). FAD, tryptophan, and NADPH (nicotinamide adenine dinucleotide phosphate) have been used as a measuring tool to see the mitochondrial metabolic response before and after therapy such as in prostate cancer (Alam et al., 2017). In cell lysate samples such as in this study, further molecular analysis is needed to determine the differences in the composition of compounds in the absorption/absorption spectrum between lysates from cancer patients.\n\n\nConclusions\n\nThe combinations of principal component analysis (PCA) and absorbance scanning were able to group patients with similar histopathology and metastasis based on their chemical compositions. Although further investigation is needed, molecular fingerprinting using absorbance scanning to predict intratumoral similarity and difference is exciting.\n\n\nData availability\n\nOpen Science Framework: Underlying data for ‘Potential use of absorbance scanning in differentiating tumor microenvironment compositions from endoscopic biopsy of colorectal cancer patients available at https://doi.org/10.17605/OSF.IO/QV7H5 (Abdullah et al., 2021).\n\nThis project contains the following underlying data:\n\n• Absorbance – Orange data.docx\n\n• UV-Vis Spectrum data.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nConsent\n\nWritten informed consent for publication of the patients’ details was obtained from the patients.\n\n\nGrant information\n\nWe thank HIBAH PUTI Q2 Universitas Indonesia (NKB4127/UN2.RST/HKP.05.00/2020) for funding our study.",
"appendix": "Acknowledgements\n\nWe thank Dr Aryo Tedjo from the Department of Medical Chemistry and Drug Development Cluster for supporting the absorbance scanning and Orange mining data analysis.\n\n\nReferences\n\nAbdullah M, Utari AP, Nursyirwan S, et al.: Potential Use of Absorbance Scanning in Differentiating Tumor Microenvironment Compositions from Endoscopic Biopsy of Colorectal Cancer Patients.2021. Publisher Full Text\n\nAlam SR, Wallrabe H, Svindrych Z, et al.: Investigation of Mitochondrial Metabolic Response to Doxorubicin in Prostate Cancer Cells: An NADH, FAD and Tryptophan FLIM Assay. Sci. Rep. 2017; 7: 10451. PubMed Abstract | Publisher Full Text\n\nBalan V, Mihai C-T, Cojocaru F-D, et al.: Vibrational Spectroscopy Fingerprinting in Medicine: from Molecular to Clinical Practice. Materials. 2019; 12. PubMed Abstract | Publisher Full Text\n\nDemšar J, Curk T, Erjavec A, et al.: Orange: Data Mining Toolbox in Python. J. Mach. Learn. Res. 2013; 14: 2349–2353.\n\nLandskron G, De la Fuente M, Thuwajit P, et al.: Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014; 2014: 149185–149185. Publisher Full Text\n\nNogueira MS, Maryam S, Amissah M, et al.: Evaluation of wavelength ranges and tissue depth probed by diffuse reflectance spectroscopy for colorectal cancer detection. Sci. Rep. 2021; 11: 798. PubMed Abstract | Publisher Full Text\n\nOudijk L, Neuhofer CM, Lichtenauer UD, et al.: Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations. Eur. J. Endocrinol. 2015; 173: 43–52. PubMed Abstract | Publisher Full Text\n\nSchillaci O, Scimeca M, Toschi N, et al.: Combining Diagnostic Imaging and Pathology for Improving Diagnosis and Prognosis of Cancer. Contrast Media Mol. Imaging. 2019; 2019: 1–10. PubMed Abstract | Publisher Full Text\n\nWang M, Zhao J, Zhang L, et al.: Role of tumor microenvironment in tumorigenesis. J. Cancer. 2017; 8: 761–773. PubMed Abstract | Publisher Full Text\n\nWei R, Liu S, Zhang S, et al.: Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers. Anal. Cell. Pathol. 2020; 2020: 6283796–6283713. PubMed Abstract | Publisher Full Text\n\nWhiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008; 27: 5904–5912. PubMed Abstract | Publisher Full Text\n\nWinkler J, Abisoye-Ogunniyan A, Metcalf KJ, et al.: Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 2020; 11: 5120. PubMed Abstract | Publisher Full Text\n\nYang P-W, Hsu I-J, Chang C-W, et al.: Visible-absorption spectroscopy as a biomarker to predict treatment response and prognosis of surgically resected esophageal cancer. Sci. Rep. 2016; 6: 33414–33414. PubMed Abstract | Publisher Full Text\n\nYuan Y, Jiang Y-C, Sun C-K, et al.: Role of the tumor microenvironment in tumor progression and the clinical applications (Review). Oncol. Rep. 2016; 35: 2499–2515. Publisher Full Text"
}
|
[
{
"id": "126731",
"date": "28 Mar 2022",
"name": "Cornelis F. M. Sier",
"expertise": [
"Reviewer Expertise biomarkers in oncology",
"including colorectal cancer"
],
"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 brief report by Murdani Abdullah and co-authors reports rather preliminary looking results of PBS- homogenates from biopsy material from 3 colorectal cancer patients which were scanned in a UV-Vis spectrophotometer from 400-1000 nm. Although the introduction focuses slightly on the tumor microenvironment there is no actual research question formulated. The cohort of samples (n=3) is definitely not enough to draw conclusions about the applicability of the method. In conclusion, this version of the manuscript does not contribute to the scientific literature.\nMinor remarks:\nThe word potential in the title seems rather opportunistic\n\nNext to a larger and more defined cohort, tissue biopsies are often rather superficial and might not represent the whole tumor.\n\nThe authors could/should consider including normal tissue adjacent to the tumor to establish the difference with the tumor within single patients.\n\nHomogenates and lysates are not synonyms, the latter usually contains a detergent.\n\nPCA analysis should be better explained.\n\nThe table needs to be extended, legends of figures need revision.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1300
|
https://f1000research.com/articles/9-1342/v1
|
18 Nov 20
|
{
"type": "Research Article",
"title": "A causal relationship model of health literacy and health behavior for obesity prevention among primary school students in Bangkok, Thailand",
"authors": [
"Ladaporn Thongsong",
"Wanida Neranon",
"Ladaporn Thongsong"
],
"abstract": "Background: The aim of the study was to develop a research instrument to study the levels of health literacy for obesity prevention (HLFOP), as well as health behavior for obesity prevention (HBFOP). In addition, we investigated the causal relationship model between health literacy and health behavior for obesity prevention among primary school students in Bangkok, Thailand. Methods: A cross-sectional study among 600 participants who were primary school students (aged 9-13 years) was conducted. The participants were selected from schools in all parts of Bangkok using multi-stage random sampling technique. The research instrument to assess HLFOP and HBFOP, constructed by the researchers, were utilized for data collection. Data were analyzed using descriptive statistics, exploratory and confirmatory factor analyses, and structural equation model through linear structural relationship. Results: We found that HBFOP was directly influenced by heath literacy in the category of Critical Literacy with an effect size of 0.65 (p < 0.01), and was indirectly influenced in the category of Basic Literacy and Interactive Literacy through Critical Literacy with effect sizes of 0.46 and 0.58 (p<0.01), respectively. The model was consistent with the empirical data, with Chi-Square=13.68, df=7, p=0.05721, RMSEA (root mean square error of approximation)= 0.040, SRMR (standardized root mean square residual)= 0.017 NFI (normal fit index)=0.99, GFI (goodness of fit index)=0.99, and AGFI (adjusted goodness of fit index)=0.97. Conclusions: HLFOP was influential on HBFOP in primary school students in the Bangkok Metropolis. The categories that were particularly influential were: 1) Basic Literacy: accessing health information skills; 2) Interactive Literacy: communication skills; and 3) Critical Literacy: media literacy and self-management skills.",
"keywords": [
"Causal Relationship Model",
"Health Literacy",
"Health Behavior",
"Obesity Prevention",
"Primary school students"
],
"content": "Introduction\n\nObesity in children has become a challenging health problem, not only in high-income countries but also in low and middle-income countries, especially in urban areas (World Health Organization (WHO), 2000). Medical evidence has recently indicated that obesity and overweight children are highly risky of acquiring various non-communicable diseases (NCDs), which can result in premature death and disability in adulthood. They can also cause serious conditions of physical and mental health in children (Society of Pediatric Nutrition of Thailand, 2014; WHO, 2000). Causes of obesity and being overweight are often due to changes in the diet and physical activity patterns, environmental and societal changes associated with urban development, and lack of supportive policies from various authorities, such as health, urban planning, environment, food processing distribution, marketing and education. The World Health Organization (WHO) reported that the global prevalence of overweight and obesity among children and adolescents aged 5–19 years has dramatically risen from 4% in 1975 to 18% in 2016. The rise has occurred similarly among both boys and girls; in 2016 18% of girls and 19% of boys were overweight (WHO, 2019).\n\nThe WHO has implemented Global Strategies on Diet, Physical Activity and Health in order to help reduce the rising level of NCDs due to the steady increase in obesity in children worldwide (WHO, 2009a). This indicates that most countries in the world, including high-, mid- and low-income nations, are suffering from obesity, which is contributing to the increasing number of cases and deaths from NCDs.\n\nIn Thailand, overweight and obese school-age children remain high and the numbers of cases increase annually in most urban areas of all regions, especially in Bangkok Metropolis (Health Systems Research, 2011; Health Systems Research, 2014; Ministry of Public Health, 2018. As compared to the global prevalence, there has been an upward trend in overweight and obese Thai children, especially those aged 6–14 years. Research has shown that the rate of obese and overweight boys has increased from 16.7% in 2009 to 26.1% in 2014, or by 56% in the five-year period higher than the global rate within 33 years (Health Systems Research, 2014). In addition, Hmosuwan & Ekphlakron (2014) conducted a survey investigating the nutrition profile of Thai children between the ages of 1 and 14 nation-wide. The findings of the study revealed that overweight and obesity prevalence in urban areas was higher than in rural areas across all age groups. The study further showed that the prevalence of obesity in children aged 6–11 years living in Bangkok was the nation’s highest rate, followed by 12.9% of children aged 12–14, while 12.1% of the latter group was overweight. This suggests that Bangkok experiences significant childhood obesity and overweightness.\n\nIn 2016, 13.1% of children aged 6–12 years were overweight or obese. A study of health behavior of Thai children aged 12 years revealed that 69.9% of them consumed snacks, soft drinks and candies during their meals; 38.9% drunk soft drinks; and 26.6% drunk soft drink for more than three days a week. Moreover, snacks and candies were consumed by 76.9% and 58.6% of respondents, respectively (Ministry of Public Health, 2016). Among those aged 10–14 years, only 27% did regular exercise, 72.3% used smartphones and computers (smartphones were most highly accessed in Bangkok compared with other areas), and 55.5% spent time playing computer games. However, children in Bangkok had insufficient intake of fruit and vegetables (Health Systems Research, 2014; Hmosuwan, 2014). Consequently, overweight and obesity in Thai children is a crucial public health problem, which needs to be urgently solved. They not only affect children’s overall health condition, but also negatively impact on the country’s economic development (Ministry of Public Health, Department of Health, 2016; Ministry of Public Health, Division of Non-Communicable Diseases, 2017).\n\nHeath literacy (HL) is a significant issue in Thailand that needs to be promoted to all age groups. The declaration of the Twelfth National Health Development Plan 2017–2021 stated that HL and health behavior (HB) were ultimate goals that needed to be increased and promoted. For instance, more appropriate exercise; consumption of more vegetables and fruits and less sweets, and fatty and salty food; purchasing quality healthy products; and reducing smoking and drinking (Ministry of Public Health, Department of Health, 2016; Ministry of Public Health, National Health Development Plan, 2016). Significantly, HL has been defined as the cognitive and social skills that determine the motivation and ability of individuals to gain, access, understand and use information in promoting good health (Nutbeam, 2000; Nutbeam, 2008; WHO, 2009a). Nutbeam divides HL into three levels, namely: basic/functional HL; interactive HL; and critical HL (Nutbeam, 2000; Nutbeam, 2008). Furthermore, Manganello (2008) included media literacy as a fourth level of HL for adolescents, since they exploit more media and technology. The author emphasized that HL can be a factor that contributes to adolescents’ positive health outcomes in relation to HB, health costs and health service use. As seen in 17 studies conducted in adults and five studies in children, low HL was found significantly related to increased body mass index (BMI), and being overweight and obese. In cases of children and adolescents, the above relationship seems to be more consistent than the studies in adults (Michou et al., 2018). Media literacy (ML) was positively related to total health promoting behavior scores, including prevention behaviors for cigarette smoking, nutritional and dieting habits, physical sedentary activity, safety and injury behaviors, and sexual behaviors (Zamir et al., 2011). According to a systematic review, 13 studies stated that HL in basic skills and ML were significantly related to adolescents’ HB, but only two studies revealed the relationship between HL and HB of adolescents. Linking HL with HB of adolescents, as suggested by Fleary et al. (2018), is an interesting issue to be further investigated for a better understanding of the HL roles of adolescents. In addition, future research should examine the system of HL by developing an effective assessment tool for adolescents’ health behavior assessment (Fleary et al., 2018; Michou et al., 2018).\n\nAs discussed above, Thai students in various regions still have low and moderate levels of HL and HB (Behavioral Science Research Institute, 2014a; Department of Health Service Support, 2016). Currently, there is insufficient information concerning HL (specifically Interactive Literacy and Critical Literacy) in primary school students (aged 9–13 years) in Bangkok Metropolis. Therefore, this study aimed to develop a research instrument to study the levels of HL for obesity prevention (HLFOP), as well as HB for obesity prevention (HBFOP) and the causal relationship model between HLFOP and HBFOP among primary school students. The research findings from this study could pave the way for curriculum development and HLFOP and HBFOP promotion among primary school students in both rural and non-rural areas.\n\n\nMethods\n\nThis research project was approved by the Institutional Review Board, Kuakarun Faculty of Nursing, Navamindrathiraj University (approval number KFN-IRB 2017-07). The research was conducted under the Ethical Standard in Human Research of the National Policy and Guidelines for Human Research of Thailand. Information about the study was explained to the students, their parents and teachers prior to conducting the study, and written informed consent to participate in the study was signed and obtained from the students and their legal parents. As approved by the Research Fund Board of the University, each student participant received 200-bath cash incentive for their participation. Permission was sought from the students’ schools to conduct the study.\n\nThis study was in two phases. In phase 1, HL and HB scales were developed to study the causal relationship model between HLFOP on HBFOP. This research instrument was validated using pilot testing. In phase 2, a cross-sectional study was conducted using the research instrument created in phase 1 on 600 primary school students to assess the causal relationship between HLFOP and HBFOP in this population.\n\nDevelopment of study instrument. To understand HLFOP and HBFOP in Thai school-aged students, a questionnaire was systematically developed by the researchers. HLFOP and HBFOP factors were first synthesized by reviewing textbooks, research studies, articles and related documents to better understand the conceptual framework and principles for the construction of appropriate models, operational definitions and factor structures.\n\nFor the HLFOP, previous research that was applicable for the present study included that conducted by Nutbeam (Nutbeam, 2008; Nutbeam, 2009) and Manganello (Manganello, 2008; Manganello et al., 2015) as well as some related previous studies in Thailand (e.g., Behavioral Science Research Institute, 2014a; Department of Health Service Support, 2016), while for HBFOP, especially applicable was the WHO’s conceptual framework on obesity prevention (WHO, 2000; WHO, 2019), the “3Es, 2Ss” (Principles of NCD Prevention) from the Thai Ministry of Public Health (Ministry of Public Health, 2016), and Principles of Medical Practice in Obesity Prevention and Treatment in Thai children by the Society of Pediatric Nutrition of Thailand (2014).\n\nValidation of study instrument. Content validity of the HLFOP and HBFOP research instrument was verified by five experts in the field of obesity, HL and HB in children and adolescents. All of the experts worked as child health specialists in Bangkok, including two child health and behavior specialists, one school health nurse, one children’s nutritionist, and one health education teacher of a primary school. After the expects checked the content validity of the research instrument, the researchers revised the instrument based on the experts’ feedback in terms of content, language use, and appropriate context representation for children aged 9–13 years in Bangkok. Index of consistence (IOC) was analyzed for criteria acceptability.\n\nA pilot test was performed with 30 primary school students in Bangkok having the same characteristics as the target participants, which were students aged 9–13 years studying in Grades 4–6 (or Prathomsuksa 4–6) in schools under the Office of Bangkok Metropolitan Administration (BMA), with the ability to read, write, and communicate with normal movement, without congenital disease of metabolic syndrome and not being in weight control programs. Reliability was analyzed using Cronbach’s alpha. The revised version of the instrument was then used for data compilation.\n\nStructure of study instrument. There are three sections of the questionnaire. Section one contains a checklist to obtain general demographic information. Section two consists of 30 items with a rating scale format to collect information about HLFOP. Section three consists of 24 items with a rating scale format to collect information about HBFOP. The items in section two and three include both positive and negative statements. The five-point Likert scale was used to find out the HL and HB level perceived by the participants in terms of the frequencies they behaved according to each statement. The five levels ranged from 5 = all the time, 4 = more often, 3 = sometimes, 2 = rarely, and 1= none.\n\nFollowing the study of Thai people, the Behavioral Science Research Institute (2014b) and the Department of Health Service Support (2016), the rules for the interpretation of the HLFOP and HBFOP scores are as follows: less than <60% indicating low level, 60–79.99% indicating moderate level, 80–100% indicating high level.\n\nParticipants. To determine an appropriate sample size to confirm a causal relationship model, the sample size-to-parameters of 20:1 proposed by Hair et al. (2010) was adopted. Since there were 30 HLFOP parameters, the sample size of the present study was 600 participants.\n\nThe 600 students were selected using multi-stage random sampling from all parts of Bangkok. For more convenient selection for research participants, the researchers categorized all parts of Bangkok, generally comprised of 50 areas in total, into three main area categories, i.e. outer, central, and inner zones. Simple random sampling was then used to select two areas from each zone, contributing to the total of six areas, and one school in each area was further selected. Lastly, stratified random sampling was adopted to sample the target student participants from the three categorized zones, resulting in 194 students from the outer zone, 252 students from the central zone, and 154 students from the inner zone..\n\nInclusion criteria: primary school students aged 9–13 years studying in Grades 4–6 (or Prathomsuksa 4–6) in schools under the Office of Bangkok Metropolitan Administration (BMA), with the ability to read, write, and communicate with normal movement, without congenital disease of metabolic syndrome and not being in weight control programs.\n\nData collection. After obtaining consent from the students and their legal parents, a group of trained research assistants coordinated with the teacher coordinators of the six chosen schools. Then the research assistants went to the participants’ schools to collect data. Before starting compiling data, the research assistants gave self-introduction, expressed the purpose of the research clearly, and clarified the data collection details (e.g., length of time, rating description) to each of the participants. After having received and understood all the research-related information, each participant was given an untimed questionnaire to complete, taking normally 25–30 minutes to respond to the given questionnaire. The research assistants then double-checked each returned questionnaire to avoid blanks or incomplete responses.\n\nDescriptive statistics were utilized for data analysis of demographic information, and responses to the HLFOP and HBFOP instrument. Reliability of the instrument was analysed using Cronbach’s alpha, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were utilized to analyse construct validity. Structural equation model (SEM) through linear structural relationship was employed to analyze a causal relationship model of HLFOP on HBFOP using LISREL 8.80.\n\n\nResults\n\nFor section two (HLFOP), the construct validity of 18 items (out of 30) were approved by EFA. Three categories were classified: Basic Literacy (4 items on accessing health information skills); Interactive Literacy (5 items on communication skills); and Critical Literacy (4 items on ML and 5 items on self-management skills). Cronbach’s alpha for each category was 0.87, 0.78, 0.84, 0.76 and 0.81, respectively. Item correlation coefficient was between 0.3–0.75. KMO = 0.928, Bartlett's Test = 3737.4 (p<0.000). Factor loading was between 0.69–0.87. The CFA was consistent with the empirical data (Chi-Square = 0.96, df =1, P-value = 0.33, RMSEA = 0.000, Standardized RMR = 0.0058, NFI = 1, Goodness of Fit Index (GFI) = 1, Adjusted Goodness of Fit Index (AGFI) = 0.99; Figure 1).\n\nChi-Square = 0.96, df = 1, P-value = 0.33, RMSEA = 0.000, SRMR = 0.0058, NFI = 1, GFI = 1 and AGFI = 0.99.\n\nFor section three (HBFOP), the construct validity of 20 items (out of 24) were approved by EFA. Three categories were classified: Eating Behaviours (12 items); Exercising Behaviours (4 items); and Emotional Control (4 items). Overall Cronbach’s alpha was 0.73. Item correlation coefficient was between 0.3–0.68. KMO = 0.863, Bartlett’s’ Test = 3412.40 (p<0.000). Factor loading was between 0.37–0.72. The CFA was found consistent with the empirical data (Chi-square = 0.00, df = 1, p-value = 0.977, RMSEA = 0.00; Figure 2).\n\nChi-square = 0.00, df = 1, p-value = 0.977, RMSEA = 0.00.\n\nA total of 600 students completed the study instrument, 246 boys (41%) and 354 girls (59%). In terms of school levels, 204 (34%) were from Prathomsuksa 4, 205 (34.2%) in Prathomsuksa 5, and 191 (31.8%) in Prathomsuksa 6. Their average age was 11.10 years (SD=0.94, Max = 13.3, Min = 9.00), with GPA= 3.39 (SD=0.51). Their average weight was 41.73 kgs (SD=13.5, Max =96, Min =20), and average height was 145.77cm (SD=9.8, Max = 176, Min =120). Most of the students (81%) resided with their parents, and 19% with relatives and other persons; 39.5% resided in rental houses and 23.8% in their own houses; 13.5% resided in flats or condominium, 6.7% in townhouses and 5% detached houses. Their parents’ marital status was as follows: 55.7% married or lived together, and 26% widowed, divorced or separated.\n\nThe total means from students for HLFOP were at low level (X¯ = 45.76, SD = 12.77), whereas HBFOP were at moderate level (X¯ = 62.72, SD = 9.17). For HLFOP, 71.5% of students were at low level, 26.5% were at moderate level, and 2% were at high level. For HBFOP, 57.66% of students were at moderate level, while 39.1% were at low level at 39.17%, and 3.17% were at high level (Table 1).\n\nThe causal relationship model (CRM) between HLFOP and HBFOP indicated that HLFOP had direct influence on HBFOP in Critical Literacy with effect size at 0.65, and indirect influence in Basic Literacy and Interactive Literacy through Critical Literacy, with effect sizes at 0.46. and 0.58, respectively (p< 0.01). For HLFOP, Critical Literacy was directly influenced by Interactive Literacy, with effect size at 0.89, and indirect influence from Basic Literacy through Interactive Literacy with effect size 0.71, (p <0.01). For HLFOP, Interactive Literacy was directly influenced by Basic Literacy with effect size at 0.80 (p < 0.01). Squared multiple correlation for SEM of HBFOP (R2) = 0.21, which indicated that variables in the model could explain variances of HBFOP at 21% (Table 2). The CRM was consistent with the empirical data, as seen in Figure 3.\n\n** p< .01\n\nChi-Square = 13.68, df = 7, P-value = 0.05721, RMSEA = 0.040, Standardized RMR = 0.017 NFI = 0.99 GFI = 0.99 AGFI = 0.97.\n\n\nDiscussion\n\nThe three factors of HLFOP included in this study, namely Basic Literacy (accessing health information skills), Interactive Literacy (communication skills), and Critical Literacy (ML and self-management skills), were consistent with the study by Tripetchsriurai and Kedcham who developed a HL scale for obesity among the secondary school students, grade 9 in Thailand, which found that HL consisted of self-management, accessing information and health care, communication for health promotion and reduction of risky health conditions, and media awareness (Tripetchsriurai & Kedcham, 2017). Our HLFOB was also consistent with Nutbeam’s three factors: Basic/Functional Heath Literacy, Interactive Heath Literacy and Critical Heath Literacy (Nutbeam, 2008), along with Manganello’s (2008) four levels of HL in adolescents (Functional, Interactive, Critical and ML). The three factors of HBFOP included in this study were Eating Behaviours, Exercising Behaviours and Emotional Control. These were consistent with the WHO (2000), “3E-2S” (Principles of NCD’s Prevention) of the Ministry of Public Health, Thailand (Ministry of Public Health, 2016), and the Principles of Medical Practices and Treatment of Obesity Prevention in Thai Children (Society of Pediatric Nutrition of Thailand, 2014).\n\nFor the HLFOP and HBFOP instrument development, the IOC values were between 0.8–1.0, which, as they are higher than 0.6 (Hambleton, 1984), were found to be acceptable. In addition, the reliability values as calculated by Cronbach’s alpha were between 0.73–0.87, which higher is than the criteria for reliability of 0.7 (Cronbach, 1990). The item correlation coefficient values were between 0.30–0.75, which is higher than the criteria of 0.2 (Hambleton, 1984). The EFA indicated that factor loading of observable factors were statistically significant, mostly higher than 0.3 (Hair et al., 2010). HLFOP contained factor loading between 0.69–0.87, whereas HBFOP was at 0.37–0.72. CFA of both scales were consistent with the empirical data. Therefore, it can be confirmed that these two scales were eligible to assess HLFOP and HBFOP in primary school students in the Bangkok Metropolis.\n\nIn the primary school students, HLFOP was primarily found to be at a low level (71.5%), with 26.5% of students showing a moderate level and 2% showing a high level. For HBFOP, most students had a moderate level (57.66%), with 39.17% at a low level and 3.17% at a high level. These findings were consistent with a previous study that indicated that HLFOP level of obese children aged 10–14 years were 60% with low levels, 38.4% with moderate, and 1.3% with high. In these children, 58.4% of children were found to have an overall HBFOP at moderate level (Intarakamhang & Intarakamhang, 2017). Mean scores of the HLFOP in all sub-scales were also found at the low level: the lowest scores were mostly found in the communication skill (82.2%), self-management skill (60.33%), media literacy (58.2%), and accessing health information skill (52.67%), which indicated that most students still maintained low level of HLFOP in all sub-scales resulting in HBFOP at moderate and low levels. Therefore, HLFOP in all factors (Basic, Interactive and Critical Literacies) should be promoted to enhance both cognitive and social skills, which encourage individual’s motivation and competencies to be able to wisely access, understand and use various information sources and keep healthy (Nutbeam, 2000; WHO, 2009b).\n\nSince children and adolescents themselves have less access to healthcare services, and their development process needs more learning skills to grow to be healthy adults, information technology can be used to promote ML and health among this population. Similarly, they take in a huge amount of information through internet access, which can be used to provide a proactive approach. This allows them to get access to useful information about health and health services available, which can reduce expenses in healthcare services when they are older. Thus, HL development is supposed to be performed based on three aspects, including individual, interaction and society with a variety of developmental models (Manganello, 2008).\n\nThis is especially true for low HL groups. There should be consideration of the needs and preferences of students or people with low HL when determining channels of health information dissemination. Implementing interventions should be considered to develop health information-seeking skills in the population and carefully prepare information and materials that are easily accessible and understandable (Manganello et al., 2017 This is shown in a study of Hausmann et al. (2017) examining the use of social media in 204 children aged 12 years and above, attending a primary care adolescent and young adult clinic. The study showed that the adolescents and the young adults valued their privacy and the protection of their personal data. It was further found that 51.5% of the participants gave out their health information on social media, 48.5% did not give out and only 25% of them believed that social media could provide them with useful health information. Few of the participants connected with their health care team on social media, while most of them did not want to use this method; texting was preferred (Hausmann et al., 2017).\n\nOur findings also confirmed the causal relationship of HLFOP influence on HBFOP. This was shown through Basic Literacy (accessing health information skill) through Interactive Literacy (communication skill), with an effect size at 0.80, through Critical Literacy (ML and self-management skill), with effect size at 0.89, and through HBFOP with effect size 0.65. These results are consistent with a study by Chang, where HL in high and low groups were correlated with HB in nutrition (Chang, 2011); children with higher HL were less likely to be obese and underweight. In addition, children who did not have regular physical activity, or have sugar-sweetened beverage intake are more likely to report being overweight or obese (Shu-Fang et al., 2016). In addition, our results are consistent with a study that showed that exercising habits were positively related to self-management and ML, at 0.01 and 0.05, respectively (Thipwong & Numphol, 2014). Our results were also consistent with the study of Intarakamhang & Intarakamhang (2017) in that HL influenced HB of obese school children, and basic literacy had an influence on HB through interactive literacy and critical literacy with effect sizes of 0.76, 0.9, and 0.55. The path analysis of HL model component revealed that HL started from health information and service access, directly passed through communication, media literacy to decision making with effect sizes of 0.63, 0.93, 0.98, and 0.05, respectively.\n\nIn our study, HLFOP had significant influences on HBFOP in terms of eating, exercises, and emotional control, resulting in better health conditions of the elementary school students. This is compatible with the theory of Behavior Modification based on Cognitive Behavior Theory in which 1) behaviors are affected by cognitive process; 2) cognitive process can be modified; 3) behavior can be modified by cognitive process changing (Dobson, 2010). This is also consistent with Bandura’s Social Cognitive Theory (Bandura, 1986) where individual behavior changes occur in a social context with a dynamic and reciprocal interaction of the person, environment and behavior. Research has shown that sport participation is related to feelings of social competence, and this relationship increases across late childhood into early adolescence. There are significant associations with sport at baseline and a significant association with sport over time on self-perceived social competence for both men and women (Bedard et al., 2020). Moreover, Manganello asserted that HL would resulted in HB, reduction in health costs, health services use, and living healthy lifestyles as evaluated by exercise, eating, emotion, smoking, drinking and drug consumption. But to succeed, individuals must be supported by policies (Manganello, 2008). This was confirmed with research showing that having strong or weak policies was significantly associated with lower BMI z-scores, lower odds of overweight or obesity, and better dietary outcomes, relative to no policy (Manganello et al., 2017).\n\nTherefore, we recommend that evaluation of HLFOP and HBFOP for primary school students should be firstly established in the National Policy and Principles of Health Development. Promotion strategies involving HL basic literacy in healthcare information should be managed in an easy way to access and understand. Social skills or interactive literacy for increasing channels of communication and learning should be practiced. ML and self-management should also be applied in the children’s daily lives.\n\nThis research should be beneficial for teachers, instructors, paediatric nurses, school health nurses and related personnel in policy planning, and formulating activities to promote HLFOP and HBFOP. Curriculum development in this aspect should be constructed for primary students in their schools and community. Finally, further research in HL and HB should be conducted. Other factors related to the contexts of individuals, societies and appropriate policy for urbanization should be studied.\n\n\nData availability\n\nUnderlying data cannot be shared as the ethical committee that approved this study states that only aggregated data can be shared openly. In addition, the consent form that parents/children signed explicitly stated that the data resulting from the study would not be openly shared. Researchers 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: A Causal Relationship Model of Health Literacy on Health Behavior for Obesity Prevention among Primary school students in Bangkok, Thailand, https://doi.org/10.17605/OSF.IO/6U7YT (Thongsong & Neranon, 2020).\n\nThis project contains the following extended data:\n\n- HLFOP and HBFOP research instrument in English\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 would like to thank the Research Fund of Navamindradhiraj University for a research grant allocated. The author would also like to thank all the students, parents and teachers for their time and participation in this research.\n\n\nReferences\n\nBandura A: Social foundations of thought and action: A social cognitive theory. Englewood Cliffs, NJ Prentice-Hall. 1986. Reference Source\n\nBehavioral Science Research Institute, Department of Health Service Support, Health Education Division: A Guide to Health Assessment for Thai Children and Overweight Youth. Nonthaburi, Thailand. 2014a.\n\nBehavioral Science Research Institute, Department of Health Service Support, Health Education Division: Assessing health literacy to prevent premature pregnancy for Thai teenagers aged 15-21 years. Nonthaburi, Thailand. 2014b.\n\nBedard C, Hanna S, Cairney J: A Longitudinal Study of Sport Participation and Perceived Social Competence in Youth. 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}
|
[
{
"id": "75778",
"date": "24 Feb 2021",
"name": "Supamas Angsuchoti",
"expertise": [
"Reviewer Expertise Statistics",
"Research and Evaluation in education"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe overview of the article is okay. But suggest to adjust slightly as follows:\nAccording to this review (Hmosuwan & Ekphlakron), the last name translates into English, as spelled like this. “Homsuwan & Ekphlakron”.\n\nPage 5 In the topic Results, Development of the research instrument. From the EFA, it should be revised to CFA because the analysis results described was CFA.\n\nPage 5 item correlation, it should be revised to item total correlation.\n\nPage 6 The EFA, it should be revised to CFA.\n\nPage 6 observable factor, it should be revised to observable variables.\n\nPage 9 about effect size 0.9, it should be revised to 0.97.\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": "6422",
"date": "21 Dec 2021",
"name": "Ladaporn Thongsong",
"role": "Author Response",
"response": "Dear Reviewer I am grateful for your guidance. Your guidance is very helpful in our study. We will be happy to modify the work according to your suggestions. Best regards, Thongsong L and Neranon W"
},
{
"c_id": "6740",
"date": "09 Jun 2021",
"name": "wanida neranon",
"role": "Author Response",
"response": "I agree with the suggestions. I will edit for suggestions."
},
{
"c_id": "7494",
"date": "21 Dec 2021",
"name": "wanida neranon",
"role": "Author Response",
"response": "Adjusted all points that have been suggested."
}
]
},
{
"id": "89153",
"date": "03 Aug 2021",
"name": "Tuyen Van Duong",
"expertise": [
"Reviewer Expertise Health literacy",
"healthy diet literacy",
"health-related behaviors",
"physical activity",
"mental health",
"health-related quality of life"
],
"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 conducted a cross-sectional study on 600 primary school students to examine the association between health literacy and health behaviors. Significant associations were found. The study was ethically conducted. The manuscript was well-developed. However, I have some suggestions and comments to improve the logic and quality of the manuscript as below.\nThis is a cross-sectional study, and you used the SEM model to test the association. I suggest not using the word “causal relationship”. The title and purpose should be revised accordingly.\n\nThe presentation of the Introduction, Methods, Results and Discussion should also be revised. The authors should refine the writing throughout the manuscript to avoid mentioning \"causal relationship\".\n\nIn Phase 1, please refer to some guidelines for the development and validation of a research tool, e.g. Boateng et al., 20181.\n\nIt is better to have a chart for sampling.\n\nFor the sampling, how did the authors approach and collect the study participants in one school? Did you have one or two more steps to recruit students by classes, grades (or age) to have a well-represented sample?\n\nWhich social demographic information did you collect? Why don’t you adjust these in the regression model?\n\nSections two and three of the questionnaire consist of positive and negative items. Authors should explain clearly which items, how to code, and calculate the score. The subdomains/subscales should also be explained (e.g. how many items are in each domain).\n\nMore details are needed in the statistical section.\n\nIn Figure 1, Figure 2, and Figure 3, there should be observational variables and latent variables. However, the authors seem to calculate the scores for subscales (e.g. media literacy, eating behavior). These are not the raw observational variables. There should be 30 items for HLFOP, and 24 items for HBFOP. Please explain and rerun the SEM models. You can add the finding in the supplementary documents if necessary.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7056",
"date": "21 Dec 2021",
"name": "Ladaporn Thongsong",
"role": "Author Response",
"response": "Dear Reviewer, I am grateful for your guidance. Your guidance is very helpful in our study. We will be happy to answer your questions and modify the work according to your suggestions. About your questions: 1. This is a cross-sectional study, and you used the SEM model to test the association. I suggest not using the word “causal relationship”. The title and purpose should be revised accordingly. Reply: I agree to revise the title and purpose that you suggest. 2. The presentation of the Introduction, Methods, Results and Discussion should also be revised. The authors should refine the writing throughout the manuscript to avoid mentioning \"causal relationship\". Reply: I agree to revise what you suggest. 3. In Phase 1, please refer to some guidelines for the development and validation of a research tool, e.g. Boateng et al., 20181. Reply: Thank you very much for the good advice and good article. This research was development and validation of research tools according to the guideline of Six-Stage Process for Structural Equation Modeling (Hair JF, Black WC, Babin BJ, et al., 2010) and many research, e.g. Zamir LD, Lemish D, Gofin R, 2011, Manganello JA, DeVellis RF, Davis TC, et al., 2015, Intarakamhang U, Intarakamhang P, 2017, Tripetchsriurai N, Kedcham D, 2017, and especially, following the study of Thai people, the Behavioral Science Research Institute (2014b) and the Department of Health Service Support (2016). However, I will follow the suggestion that refers to some guidelines for the development and validation of a research tool into the revised article. 4. It is better to have a chart for sampling. Reply: Described in Article 5. 5. For the sampling, how did the authors approach and collect the study participants in one school? Did you have one or two more steps to recruit students by classes, grades (or age) to have a well-represented sample? Reply: The 600 students were selected using multi-stage random sampling from all parts of Bangkok. For a more convenient selection for research participants, the researchers categorized all parts of Bangkok, generally comprised of 50 areas in total, into three main area categories, i.e. outer, central, and inner zones. Simple random sampling was then used to select two areas from each zone, contributing to the total of six areas, and one school in each area was further selected. Lastly, stratified random sampling was adopted to sample the target student participants from the three categorized zones, resulting in 194 students from the outer zone, 252 students from the central zone, and 154 students from the inner zone. Inclusion criteria: primary school students aged 9–13 years studying in grades 4–6 (or Prathomsuksa 4–6) in schools under the Office of Bangkok Metropolitan Administration (BMA), with the ability to read, write, and communicate with normal movement, without congenital disease of metabolic syndrome and not being in weight control programs. As a chart for sampling. 6. Which social demographic information did you collect? Why don’t you adjust these in the regression model? Reply: The aim of the study was to develop a research instrument to study the levels of health literacy for obesity prevention (HLFOP), as well as health behavior for obesity prevention (HBFOP), investigating the causal model between health literacy and health behavior for obesity prevention among primary school students in Bangkok, Thailand. Thus, the presentation of this research focuses on the causal model. However, that is a good suggestion for the new issue. 7. Sections two and three of the questionnaire consist of positive and negative items. Authors should explain clearly which items, how to code, and calculate the score. The subdomains/subscales should also be explained (e.g. how many items are in each domain). Reply: Thank you for the good advice. About the tool subdomains/subscales that has been verified. Some of them have already been explained in the results section. However, I will explain further as suggested in the revised article. 8. More details are needed in the statistical section. Reply: Described in Article 9 9. In Figure 1, Figure 2, and Figure 3, there should be observational variables and latent variables. However, the authors seem to calculate the scores for subscales (e.g. media literacy, eating behavior). These are not the raw observational variables. There should be 30 items for HLFOP, and 24 items for HBFOP. Please explain and rerun the SEM models. You can add the finding in the supplementary documents if necessary. Reply: Because the aim of the study was to develop a research instrument to study the levels of health literacy for obesity prevention (HLFOP), as well as health behavior for obesity prevention (HBFOP), investigated the causal model between health literacy and health behavior for obesity prevention among primary school students in Bangkok, Thailand. Therefore, it is expected that we will have quality tools based on research (HLFOP and HBFOP) that can be used for the assessment of Thai children in Bangkok. In the article, the development process and validity and reliability of the instrument are presented in phase 1 and after phase 2. In Phase 2, the researchers used quality tools obtained from Phase 1 to collect data with a sample of 600 students. After Phase 2, the tools were brought to check the quality again (the reliability of the instrument was analyzed using Cronbach's alpha and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were utilized to analyze construct validity). Figure 1, Figure 2, Figure 3, reports only the results of the instruments that passed the quality check after phase 2. Results Development of the research instrument, HLFOP, the construct validity of 18 items (out of 30) were approved by EFA. Three categories were classified: Basic Literacy (4 items on accessing health information skills); Interactive Literacy (5 items on communication skills); and Critical Literacy (4 items on ML and 5 items on self-management skills). Cronbach’s alpha for each category was 0.87, 0.78, 0.84, 0.76 and 0.81, respectively. Item correlation coefficient was between 0.3–0.75. KMO = 0.928, Bartlett's Test = 3737.4 (p<0.000). Factor loading was between 0.69–0.87. The CFA was consistent with the empirical data (Chi-Square = 0.96, df =1, P-value = 0.33, RMSEA = 0.000, Standardized RMR = 0.0058, NFI = 1, Goodness of Fit Index (GFI) = 1, Adjusted Goodness of Fit Index (AGFI) = 0.99; Figure 1). Results Development of the research instrument, HBFOP, the construct validity of 20 items (out of 24) were approved by EFA. Three categories were classified: Eating Behaviours (12 items); Exercising Behaviours (4 items); and Emotional Control (4 items). Overall Cronbach’s alpha was 0.73. Item correlation coefficient was between 0.3–0.68. KMO = 0.863, Bartlett’s’ Test = 3412.40 (p<0.000). Factor loading was between 0.37–0.72. The CFA was found consistent with the empirical data (Chi-square = 0.00, df = 1, p-value = 0.977, RMSEA = 0.00; Figure 2). For Figure 3, a causal model of HLFOP on HBFOP. Best regards, Thongsong L. and Neranon W."
},
{
"c_id": "7495",
"date": "21 Dec 2021",
"name": "wanida neranon",
"role": "Author Response",
"response": "The title, purpose, and manuscript have been revised accordingly not using the word “causal relationship”. Refers to some guidelines for the development and validation of a research tool into the revised article. Add a chart for sampling. Participants. Figure 1. Explain the structure of the study instrument, sections two and three of the questionnaires about positive and negative items. Amount of item and calculate the score. The unmodified parts were old Figure 1, Figure 2, Figure 3, (new version of Figure 2, Figure 3, Figure 4) because of reports only on quality instruments that passed the quality check after phase 2, according to the research objectives to develop a research instrument to study the levels of HLFOP, as well as HBFOP."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1342
|
https://f1000research.com/articles/10-1299/v1
|
21 Dec 21
|
{
"type": "Research Article",
"title": "Multivariate analysis and characterization of low impact crime in Mexico City",
"authors": [
"Johny Pambabay-Calero",
"Sergio Bauz-Olvera",
"Rubén Flores-González",
"Carlos Piña-García",
"Sergio Bauz-Olvera",
"Rubén Flores-González",
"Carlos Piña-García"
],
"abstract": "Background: Multivariate analysis is fast becoming a key instrument that can be used to address crimes or incidents. It may be helpful to assess government policies on crime prevention. Methods: To distinguish between the 25 official crime categories reported in Mexico City (Jan 2019 - Jun 2019), principal coordinates analysis was used to determine the quality of a characteristic in this context. This study used cluster analysis via K-means and Biplot based on time and location in terms of crime occurrence. Results: The results obtained from this preliminary analysis indicates that around 70% of crime occurrence is shown in the following boroughs: Cuauhtémoc, Iztapalapa, Gustavo A. Madero, Benito Juárez, Álvaro Obregón, Coyoacán, and Miguel Hidalgo. Conclusion: There are two factors that contribute to the difficulties in crime analysis in Mexico City, namely, the lack of people’s trust in authorities and the insufficiency of tools for data analysis. The latter is an integral part in achieving justice for the victims of crimes because it impedes the process of observing patterns and predicting the perpetrators’ next actions, which may help in solving a number of types of crimes. It is then imperative for law enforcement to utilize data analysis tools that aid in identifying crime patterns and trends, such that the occurrences of crime show a downward trend and consequentially increase the people’s trust in law enforcement agencies.",
"keywords": [
"biplot",
"crime analysis",
"k-means clustering",
"multivariate analysis",
"principal coordinates analysis"
],
"content": "Introduction\n\nLack of meaningful crime data has existed as a social problem for many years in Mexico City. However, there is a growing interest in extracting useful knowledge from data related to crime reports. Crime analysis is a major problem due to the lack of trust in authorities and insufficiency of data. Therefore, statistical methods and applications of pattern discovery are necessary to study the impact of crime on communities. In this regard, it would be necessary and advisable to provide important insights into data crime analysis (Chadee et al., 2019). Hence, it could conceivably be hypothesized that these results could be used to prevent crime and to develop tailored strategies to tackle crime and gradually build community trust.\n\nIt should be noted that this type of research involves a multidisciplinary approach i.e., different academic disciplines including social sciences, statistics, economics, and data science are combined to provide the necessary knowledge, skills, and confidence to analyze and compute data related to crime. Thus, statistics becomes a fundamental discipline to gain insights in terms of displaying, analyzing, interpretating, and presenting data.\n\nThis manuscript reviews the evidence for official crime data in Mexico City with the aim to determine the extent of crime occurrences and identify statistical features that permit us to establish variables that can provide the basis for quantitative characterization of crime reports (D’ancona and Ángeles, 1999). It is hoped that this research will contribute to a deeper understanding of crime analysis through the data availability provided by the government of Mexico City (Procuraduría, 2018).\n\nRecently, researchers have shown an increased interest in data collection methods to predict and analyze criminal behavior (Aghababaei and Makrehchi, 2016; Malleson and Andresen, 2015; Wang and Gerber, 2015). However, most of these studies have been carried out in the U.S.A. (Chen, Cho, and Jang, 2015; Flores, 2017; Yadav et al., 2019; Yang et al., 2018). Another interesting study was based on methamphetamine-related crime using Google trends (Gamma et al., 2016). Similarly, there is a growing body of literature that recognizes the importance of using social networks analysis as data sources (D’Avanzo et al., 2017). Recently researchers have examined the effects of crime patterns and antisocial behavior in Mexico City through Big Data-driven models for predicting crime rates (Piña-García and Ramírez-Ramírez, 2019).\n\nIn Mexico City, there is an urgent need to address the safety problems caused by antisocial behavior. In this context, the main disadvantage of crime analysis in Mexico City is the lack of trust in authorities and insufficiency due to a lack of reliable data. Another common obstacle faced by many researchers is the inaccurate way in how crime reports in Mexico City have been recorded. Most of these records show a low-quality dataset that involves significant issues such as: missing data, human errors, and inconsistencies in crime information. Despite the limitations mentioned above, it is still possible to obtain and identify the variability of crime trends (Arango, 2003).\n\nIt is important to note that traditional surveys are still an acceptable and reliable proxy to explore opinion about crime occurrence among citizens. These studies are mainly carried out by the National Survey of Victimization and Perception on Public Safety1 [ENVIPE], the Victimization and Institutional Effectiveness Survey2 [ENVEI], the National Institute of Statistics and Geography3 [INEGI] and the Center for Educational Research and Development4 [CIDE] (Bergman and Sarsfield, 2009; Jasso López, 2013; Vilalta-Perdomo, 2010). In this regard, there is still uncertainty in these surveys-based studies as they may be biased due to inaccurate information e.g., false rumors, fake news, and hoaxes (Cisneros and Cunjama-López, 2011).\n\nIt was after the Mexico City elections in 2018 and the open data initiative proposed recently by the Mexico City government that it was possible to gain access to crime reports committed from Jan 2019 - Jun 2019 (Piña-García and Ramírez-Ramírez, 2019). This dataset shows a significant enhancement in terms of data structure, updated information, geolocated info, and computing performance. By providing a new approach mainly based on an open policy, the Mexico City government have released a significant amount of data related to crime reports that contain information such as date, location, and category of crime, among others.\n\nMuch of the previous research on crime analysis has been exploratory in nature. A significant analysis and discussion paper on the subject was presented by Fuentes-Flores and Sánchez-Salinas (2015). This research examined the use of institutional data to provide information on crime activity. Likewise, one longitudinal study found that homicide prevalence is associated to those places located around areas that are not occupied or lived in by people (Fuentes-Flores, 2015). Auto parts theft has been linked to social aspects such as: lack of scholars degree (lack of further education) and density of population (Sánchez-Salinas and Fuentes-Flores, 2016). In addition, Vilalta (2011) examined the trend in auto parts theft and described its regular fluctuations along short periods of time. In a previous study (Vilalta-Perdomo, 2009), it was observed that firearm carrying, the hour of the day, and offender prevalence were linked to the degree of violence displayed in criminal aggressions.\n\nIt is important to note that previous studies on crime exploration have highlighted several social factors such as: friendship networks on a local level, social relegation, ethnic and racial characteristics, and breakdown of parental relationships (Kubrin and Weitzer, 2003; Sampson and Groves, 1989; Felson and Clarke, 1998).\n\nTo better understand the mechanisms of crime patterns and its effects, Clarke (2016) analyzed data from the routine activity theory perspective to determine how crime occurs when three elements converge: (1) a motivated offender, (2) a suitable target, and (3) the absence of a capable guardian.\n\nThis study systematically reviews the Mexico City crime data with the aim to evaluate the impact of crime occurrence in an in-depth statistical analysis to identify spatio-temporal patterns of crime. In addition, this manuscript attempts to show that there are crime categories with a high rate of concentration. Thus, this research should make an important contribution to develop and encourage tailored strategies to tackle crime, and to evaluate government programs or policies related to crime prevention (Bandrés and Díez-Ticio, 2001).\n\nThe rest of the paper is structured as follows. The methods section is concerned with the techniques that are used in the statistical analysis for this study. Preliminary results will be given in a systematic and detailed way in the results section. Finally, a summary explaining the significance of these findings will be highlighted in the conclusions section.\n\n\nMethods\n\nOne of the most well-known tools for identifying historic data, patterns, and trends is descriptive analytics. These analytic techniques are intended to identify measure of central tendency and statistical distribution. Moreover, there are methods such as principal co-ordinates analysis (PCoA) and K-means clustering that may be useful when a-priori knowledge is vague and cannot be fully described. These two techniques mentioned above will be our proposed framework for this study.\n\nThe biplot graph in the context of principal coordinates analysis is one of the more practical ways of displaying observations and variables of multivariate data in the same plot (Gabriel and Odoroff, 1990; Gower, 1966). In this regard, samples are displayed as points while variables are displayed either as vectors, linear axes, or nonlinear trajectories. In the case of categorical variables, category level points may be used to represent the levels of a categorical variable (Pambabay-Calero et al., 2018).\n\nIn order to identify antisocial behavior and crime patterns, the Mexico City Police Department recorded 115,209 offenses from January 2019 to June 2019 through the Portal de Delitos del Departamento de Policía de la Ciudad de México web page.5 This information related to crime reports was made accessible to the public and shared via (Procuraduría, 2018). The procedure for generating the data was as follows:\n\n• Access the Mexico City Police Department Crime Portal web page.5\n\n• Access to Mexico City FGJ investigation folders.6\n\n• Select the time period to the 1st January to 30th June 2019, due to the reclassification of crimes in July 2019.\n\nFigure 1 provides a flowchart about our three stages approach: 1. Understanding, data gathering, and preparation from the Portal de Datos de la Ciudad de México web site (in order to get the data in the best format for multivariate statistical analysis). The data were organized in such a way that the variables were the columns and the observations (crime report) as rows. The first row represented the variable titles. Also, the data set has an identifier (research folder code); 2. Discovery, data cleansing, filtering, and transformation (dealing with missing values, dealing with outliers, correcting typos, grouping sparse classes, dropping duplicates). In this step, the identified data errors are corrected to create complete and accurate data sets that are ready to be processed and analyzed. For example, faulty data was removed or manually fixed, missing values are filled in, and inconsistent entries are harmonized. 3. Application, analysis using PCoA and K-means, discussions, and conclusions (visually analyze the results of the clustering using the rstudio software (R Core Team, 2018) and drawing a rough conclusion on how k-means clustering and PCoA performs on dataset).\n\nWe analyze the impact of low impact crime in Mexico City based on 25 official categories identified from the Mexico City FGJ investigation reports: abuse of power (AOPOW), abuse of trust (AOTRU), assault and battery (AABAT), burglary of home (BOHOM), business burglary (BOBUS), dispossession (DISPO), domestic violence (DOVIO), extortion (EXTOR), forgery of public documents (FOPDO), fraud (FRAUD), identity theft (IDTHE), injuries caused by a crash due to negligent or reckless driving (ICDRV), low impact crime (LOW), malicious property damage (MPDAM), minor drug trafficking (MDTRA), sexual assault (not rape) (SEXAT), negligent or reckless damage of a vehicle while driving (DADRV), robbery of minor belongings (PTHEF), petty theft of property inside a vehicle (THOVE), robbery to passenger of public transport with violence (RPVIO), robbery to passenger or driver of a private vehicle with violence (RVVIO), theft of auto-parts (THAPA), theft of bicycle or similar (THBIC), threats (THREA), and other offenses (OTHER). 25 categories were selected as five categories had very low percentages and were therefore categorized together into other offences (OTHER). We compare and analyze how people report a crime through the traditional system of the Mexico City Police department K-means Clustering via Principal Component analysis and using multivariate statistical analysis (see extended data, Table 1 for abbreviations) (Pambabay-Calero, 2021).\n\nDue to a large number of crime categories, in this study, we will use treemap graphs, which are perfect for displaying large amounts of hierarchical structure data (tree structure). This diagram is ideal for displaying hierarchies since it presents information in a compact and space-saving way.\n\nA data set with 115,209 records was collected from the Mexico City police department reports were used for multivariate statistical analysis (Pambabay-Calero, 2021). The data set consisted of the following variables: year of the crime, month of the crime, day of the crime, crime, crime category, boroughs, prosecutor's office, time of the crime, sex of the victim, and age of the victim. The following variables were excluded from the analysis: agency, investigation unit, the neighborhood of the crime, street of the crime, longitude and latitude, as they did not provide relevant information for the present study.\n\nPCoA provides a means of exploring and visualizing similarities or dissimilarities of data. One advantage of PCoA is that it starts with a similarity matrix or dissimilarity matrix and assigns for each item a location in a low-dimensional space (Kruskal, 1964a, 1964b) by means of a biplot. For this study, axis 1 (PCoA1) characterizes the municipalities where the highest number of crimes occur, and axis 2 (PCoA2) shows the municipalities where the occurrence of crimes is very low. The term biplot refers to the simultaneous consideration of both the column space and the row space of the data matrix X. In general terms, the PCoA algorithm is mainly based on a classical approach related to multidimensional scaling (MDS) (Wickelmaier, 2003), where the main purposes are the following.\n\n• To represents the similarities of data as distances in space (coordinates) to make them accessible to visual inspection and exploration.\n\n• To verify if the differences, which distinguish some objects from others, are reflected in the representation obtained.\n\n• To discover the relevant dimensions, present in the similarities.\n\n• To explain the criteria of the similarities in terms of a rule that \"emulates\" a particular type of distance.\n\nIn this regard, we follow the traditional algorithm where matrix X (data matrix) can be derived into B = XX′ = LΛL′ through singular value decomposition, where Λ represents the diagonal matrix of the eigenvalues of B, and L the normalized eigenvector matrix. The procedure can be summarized in the following steps\n\n• Compute the distance matrix D and D2 (or also the dissimilarity matrix ∆ and ∆2).\n\n• Apply the double centering on the matrix to obtain the matrix B, i.e.,\n\n• Obtain the eigenvalues of B, according to the spectral decomposition, i.e., B = XX′ = LΛL′.\n\n• Let r be the dimensionality of the solution. The matrix ∆1 denotes the diagonal matrix with the first r positive eigenvalues and L1 the first r columns of L. Then the coordinate matrix, from the scaling, is given by X=L1Λ11/2\n\nTraditionally, crime data has been assessed by measuring clustering analysis. Thus, we carried out a k-means clustering method with the aim to find clusters of comparable spatial extent. In this context, this manuscript followed the algorithm proposed in Joshi, Sabitha, and Choudhury (2017). The procedure consists of finding the partition with the smallest error, moving individuals from one cluster to another until the reduction of the partition error stabilizes. In short, it is a matter of relocating the individuals so as to obtain clusters with the lowest possible variability. The following is the strategy followed by k-means.\n\n• Choose the first k objects in the sample as the initial k sets of mean vectors.\n\n• Choose the most distant objects.\n\n• Start with a value of k as large as necessary and proceed to form centroids of the groups spaced at a multiplot of standard deviation on each variable.\n\n• Label the objects from 1 to n and choose the ones marked with the following numbers nk,2nk,⋯,k−1nandn.\n\n• Choose k and the initial group configuration based on prior knowledge of the problem.\n\nThe following variables were used for this algorithm: days of the week, sex of the victim, category of the crime, and age group. For the selection of the number of clusters, we analyzed the silhouette coefficient (Yuan and Yang, 2019), which shows that, with six clusters, the data are correctly adjusted.\n\n\nResults\n\nIn order to understand how crime patterns occur in Mexico City, a series of measurements were performed. First, a percentage analysis on the principal official crime categories was depicted in Figure 2, where low impact crime (LOW) showed the highest percentage (see extended data, Table 1 for abbreviations) (Pambabay-Calero, 2021).\n\nGiven that the LOW category is the greatest with 76%, it becomes necessary to study this category with a different level of granularity. Figure 3 shows these sub-categories for LOW as determined by the laws of the country of Mexico.and their percentages (Table 1). It should be noted that OTHER - other offenses (unclassified information) has the highest proportion with nearly 20%, followed by DOVIO - domestic violence at 13.26%, BOBUS - business burglary at 8.97%, and THREA - threats at 7.32%.\n\nMoreover, by using principal co-ordinates analysis (PCoA) in a low dimensional space, we carried out a PCoA on the following variables: crime, time, and location (see extended data, Table 2 for abbreviations) (Pambabay-Calero, 2021). This analysis permits to observe similarities between those variables. Thus, it can be seen in Figure 4 that DOVIO - domestic violence is well clustered with locations as Cuauhtémoc and Iztapalapa in the following time (in hours): 12pm - 15pm, 15pm - 18pm and 18pm - 21pm. The other cluster is formed by the rest of the 24 crime categories, i.e., AOPOW, AOTRU, AABAT, BOHOM, BOBUS, DISPO, EXTOR, FOPDO, FRAUD, IDTHE, ICDRV, LOW, MPDAM, MDTRA, SEXAT, DADRV, PTHEF, THOVE, RPVIO, RVVIO, THAPA, THBIC, THREA and OTHER.\n\nWith the aim to gain insights about between the aforementioned crime categories; we display a biplot graph in Figure 5; in this figure it can be noted that the crimes for domestic violence, negligent or reckless damage of a vehicle while driving, and malicious property damage, present the highest level of correlation. Similarly, these categories are highly correlated with the time window of 21pm to 6am, mostly on Sundays. These results were obtained with the databases (see underlying data database_of_victim_complaints.xlsx, Pambabay-Calero, 2021).\n\nIt is important to note that locations with the highest rate of crime are depicted on axis 1 (PCoA1) at these locations; Cuauhtémoc, Iztapalapa, Gustavo Madero, Benito Juárez, Coyoacán, and Miguel Hidalgo.\n\nIn addition, Figure 5 on axis 2 (PCoA2) reveals that domestic violence and assault and battery crimes increase on Sundays between 3am to 6am. In the same Figure, about axis 1 (PCoA1), it is noted that the time of highest crime incidence is between 18 and 21 hours in Gustavo Madero and Coyoacán.\n\nIn Cuauhtémoc the most frequent crime is petty theft of property inside a vehicle in the period 15pm - 18pm. Meanwhile, the same crime increases in Benito Juárez and Miguel Hidalgo from 6am - 9am. Finally, Iztapalapa shows that the highest occurrence of crime is cases of dispossession between 6am - 9am.\n\nIt should be highlighted that LOW behavior might be measured in terms of locations and time as well. The correlation between location and time is showed in a tree map with the aim to provide a comparative analysis based on proportions. Figure 6 compares the results of the correlational analysis based on weekdays and locations. As can be seen from the figure, Cuauhtémoc, Iztapalapa, and Gustavo A Madero, have the highest number of low impact crimes. A closer inspection of the tree map shows that proportionally speaking these crimes take place from Wednesdays to Saturdays.\n\nSimilarly, Figure 7 shows a tree map with the time interval for the top three locations: Cuauhtémoc, Iztapalapa, and Gustavo A. Madero. From this data, we can see that the number of low impact crimes committed has the highest proportion from 9am to 15pm.\n\nThe results of this study indicate that it is possible to find correlations in terms of crime, time, and day across all locations included in this study. Through a k-means clustering analysis, six clusters were proposed to group LOW categories into coherent themes depicted in Figure 8. Themes were defined by the authors after the clustering analysis was performed and a discussion was held about the common characteristic of crime categories in each cluster. In theme one it is possible to find those categories related to ‘mobility’ from 12pm to 15pm across all regions: injuries caused by a crash due to negligent or reckless driving, robbery to passenger of public transport with violence, robbery to passenger or driver of a private vehicle with violence, theft of auto-parts, theft of bicycle or similar, extortion, and abuse of power. Though extortion and abuse of power are not mobility crimes per se, they could be related to misbehavior by police officers in charge of mobility surveillance. These crimes are mostly associated to men and women between 15 and 24 years old. There is no evidence of a particular day of the week where these crimes occur more frequently.\n\nIn theme two, most of the crimes are linked to the ‘burglary of home’ category. In this context this crime presents the highest number of occurrences around 9am-12pm mostly on Fridays, Saturdays, and Sundays. There is no association between the sex and age of the victim and the crime. Theme three ‘theft from stores or parked vehicles’ consisted of the crimes of business burglary, identity theft, petty theft of property inside a vehicle, and malicious property damage.\n\nThese crimes present the highest number of occurrences mostly on Tuesdays, Wednesdays, and Thursdays between the hours of 6am-9am. There is no association between the sex and age of the victim and the crime.\n\nRegarding to theme four, ‘crimes against vulnerable people’, the crimes of sexual assault (not rape), threats, fraud, abuse of trust, dispossession, and petty theft are the most frequent crimes. The most frequent victims are in between 0-14 years old and greater than 65 years old. There is no evidence of a particular day of the week where these crimes occur more frequently.\n\nWith respect to theme five, ‘weekend crimes’, the most frequent crimes are as follows: negligent or reckless damage of a vehicle while driving, forgery of public documents, and assault and battery; these crimes have the greatest occurrence on Mondays from 3am-6am. There is no association between the sex and age of the victim and the crime\n\nFinally, theme six provides those crimes related to ‘minor drug trafficking, and domestic violence’. In this case, most of the victims are in between 25 and 64 years old and the highest rates of these crimes happen between the hours of midnight to 3am. There is no association between the sex of the victim and the day of the week with the crime.\n\n\nDiscussion\n\nThe present results are another test of the routine activity theory of crime. In a city as large as Mexico City, stereotyped situations that facilitate minor crime are produced in a routine fashion related to well scheduled mass activities such as work or leisure. There is a clear difference in crime occurrence between the central city district Cuauhtémoc —which concentrates offices, malls, restaurants, and touristic locations (Gasca-Zamora, 2017; Salas-Benítez and López-López, 2019) — and a peripheral district, Iztapalapa, which houses about a fifth of the city dwellers, in conditions of social vulnerability (Rodríguez-Cortés, 2017). As the weekend sets in, a sort of wave of crime moves from the peripheral areas towards the central areas of the city.\n\nThese findings support the literature that relies on routine activities theory to explain why crime concentrates in particular spaces at particular times (e.g., Campedelli, Aziani, and Favarin (2021); Schnell, Grossman, and Braga, 2019; Vilalta et al., 2018). Explanations are reduced to the interaction of three main factors, the presence of victims, the presence of offenders, and the absence of authority. Yet, the spatial location of victims and offenders is not static and so, the matter of mobility of victims and perpetrators is a field of study that has not been thoroughly explored.\n\nIn relation to mobility, the characterization developed in this study, may mean one of two things: either offenders follow the displacements of victims, or different offenders target victims as they develop different activities within the city. Also, the activities of victims follow a general work-leisure cycle. Song et al., (2019) state that though the mobility of law-abiding citizens determines the characteristics of crime location, offenders seem to act not far from their neighborhoods, thus supporting the hypothesis of victims falling to offenders living in different parts of the city. However, further studies are needed to assess the matter.\n\nIn terms of public policy, our research envisions the possibility to use recent data to organize crime in situational categories which could help improve police efficiency.\n\nThe divulgation of these situational categories could also help non-governmental organizations (NGOs) that help victims of crime or that stand for a better access to justice, to push for changes in prevention policies and to inform citizens about situational risks and possible preventive measures.\n\nA deep sociological analysis of the cost-benefit of placing a complaint is required to disentangle the true characteristics of crime from those characteristics related to the operation of prosecuting offices in Mexico; for example: schedules of prosecution offices, location of prosecution offices, documentation needed to file a complaint, availability of prosecution clerks, and other considerations that may tamper the quality of the data available for analysis. In this study, sociological considerations of routines related to crime reporting are not considered, and that is a serious limitation of this and other similar studies.\n\nThe National Victims Survey in Mexico (ENVIPE) states that an investigation folder (such as the ones used in this research to get data) filed in a prosecution office has only in 7.9% of the actual offenses committed (INEGI, 2020). Thus, data gathered from prosecution offices must be combined with data from surveys in order to obtain a more accurate panorama of crime, particularly in highly underreported offenses, such as domestic violence and extortion (INEGI, 2020; Saavedra-Hernández, 2009).\n\nThis situational categorization, however, is incomplete without data about police behavior or observations about security measures taken by the state in specific locations to prevent minor crime. Such observations would cover the “absence of a capable guardian” part stated by the routine activities theory. Some reflections on the matter have been made with regards to the effectiveness of the use of video cameras against non-violent crime (Vilalta et al., 2018). Yet, considering the amount of crime observed and its regularity, the absence of capable guardians may be the rule and not the exception in the city.\n\n\nConclusions\n\nThe aim of the present research was to examine how crime reports can be used as an acceptable proxy measure of antisocial behavior, this data was captured in the database (database_of_victim_complaints.xlsx) and graphs 4 through 8 were generated from the file (victim_data_figures_4_8.xlsx) (Pambabay-Calero, 2021). It should be noted that by using this sort of information it is possible to find unsafe areas in Mexico City; and to estimate crime occurrence peaks as well.\n\nThis study has identified those city boroughs that show the highest number of reported crimes in terms of low impact crime. In this context, our preliminary results can be helpful to develop tailored strategies to tackle crime.\n\nThe findings of this study suggest that Cuauhtémoc and Iztapalapa show high rate of criminal acts due to their demographic factors. This observation may support the hypothesis as Iztapalapa has the highest population density and social relegation. On the other hand, despite the fact that Cuauhtémoc presents a similar population density, its levels in growth and change in terms of human development are more than acceptable in comparison with Iztapalapa (Ángeles-Castro, 2013; Caudillo and Flores, 2016).\n\n\nData availability\n\nOpen Science Framework (OSF). charactLowImpact. https://doi.org/10.17605/OSF.IO/PT3GV. (Pambabay-Calero, 2021).\n\nThis project contains the following underlying data:\n\n- Data file 1. database_of_victim_complaints.xlsx, (data on complaints collected from source including dates, age, gender, type of crime, crime description and location)\n\n- Data file 2. victim_data_figures_4_8.xlsx, (data to generate graphs in figures 4, 5, 6, 7, 8)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOpen Science Framework (OSF): charactLowImpact. https://doi.org/10.17605/OSF.IO/PT3GV. (Pambabay-Calero, 2021).\n\nThis project contains the following extended data:\n\n• Table 1. (Description and abbreviation of low impact crimes).\n\n• Table 2. (Abbreviations of municipalities).\n\n• Figure 1. (Methodology flowchart).\n\n• Figure 2. (Percentage of crime categories).\n\n• Figure 3. (Sub-categories related to low impact crime category).\n\n• Figure 4. (Principal Coordinates Analysis in two dimensions on the following variables: crime, time and location).\n\n• Figure 5. (Biplot in two dimensions of the variables: crime, time, and location).• Figure 6. A comparative analysis based on the proportions of low crime occurrence according to location.\n\n• Figure 7. A comparative analysis based on the proportions of low crime occurrence according to the time.\n\n• Figure 8. K-means cluster analysis.\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\nWe are greatly indebted to anonymous referees for many helpful comments.\n\n\nReferences\n\nAghababaei S, Makrehchi M: Mining social media content for crime prediction. 2016 ieee/wic/acm international conference on web intelligence (wi). 2016; (pp. 526–531). Publisher Full Text .\n\nÁngeles-Castro G: Crecimiento económico y desarrollo humano en la ciudad de México con respecto a un entorno nacional: una perspectiva neoclásica y dualista. Economía Sociedad y Territorio. 2013; 13(42): 431–457. Publisher Full Text\n\nArango A: Indicadores de Seguridad Pública en México: La Construcción de un Sistema de Estadísticas Delictivas.2003. Reference SourcePublisher Full Text\n\nBandrés E, Díez-Ticio A: Delincuencia y acción policial. un enfoque económico. Revista de Economía Aplicada. 2001; 9(27): 5–33.\n\nBergman M, Sarsfield R: Encuesta de Victimización y Eficacia Institucional (ENVEI) - Informe Anual 2008. 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Denmark: Aalborg University; 2003; 46 (5): 1–26.\n\nYadav N, Kumar A, Bhatnagar R, et al.: City crime mapping using machine learning techniques. International Conference on Advanced Machine Learning Technologies and Applications. 2019; (pp. 656–668).\n\nYang D, Heaney T, Tonon A, et al.: Crimetelescope: crime hotspot prediction based on urban and social media data fusion. World Wide Web. 2018; 21(5): 1323–1347. Publisher Full Text\n\nYuan C, Yang H: Research on K-Value Selection Method of K-Means Clustering Algorithm. J. 2019; 2(2): 226–235. Publisher Full Text\n\nPambabay-Calero J: charactLowImpact. Open Science Framework.2021, September 14. Publisher Full Text\n\n\nFootnotes\n\n1 https://www.inegi.org.mx/programas/envipe/2019/\n\n2 http://hdl.handle.net/10089/16309\n\n3 https://www.inegi.org.mx\n\n4 https://www.cide.edu\n\n5 https://datos.cdmx.gob.mx\n\n6 https://archivo.datos.cdmx.gob.mx/fiscalia-general-de-justicia/carpetas-de-investigacion-fgj-de-la-ciudad-de-mexico/carpetas_ss_junio2020.csv"
}
|
[
{
"id": "118447",
"date": "18 Jan 2022",
"name": "Nathalia Tejedor Flores",
"expertise": [
"Reviewer Expertise Multivariate analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript: “Multivariate analysis and characterization of low impact crime in Mexico City”. The main objective of this article is to determine the extent of crime occurrences and identify statistical features that permit us to establish variables that can provide the basis for the quantitative characterization of crime reports.\nThe reasons why I gave this article the status of “approved”, are as follows:\nThe writing style is concise with no repetition or padding, and the manuscript kept the interest throughout the sections and is well structured.\n\nDoes the title accurately summarise the content?\nThe title “Multivariate analysis and characterization of low impact crime in Mexico City”, summarises the content accurately.\n\nNew, original ideas or research findings?\nThis article presents two multivariate methods that uses crime in Mexico City data to know the basis for the quantitative characterization of crime reports, which is interesting to know.\n\nDoes it integrate tested ideas into a practical theory or model?\nYes, the manuscript integrates tested ideas into a practical theory or model.\n\nAre related or competing explanations acknowledged?\nYes, the manuscript has related explanations acknowledged.\n\nIs the argument readily apparent and clear to the reader?\nYes, the argument is readily apparent and clear to the reader, the authors present a clear explanation of the methodology and results.\n\nAre all relevant sources (stated or unstated) acknowledged?\nYes, all relevant sources are well-acknowledged.\n\nThe only correction or clarification to be made by the authors is as follows:\n\nThis article presents multivariate methods (principal co-ordinates analysis (PCoA) and Biplot), but on page 5 in the section of methods the author mention Principal components analysis (PCA), is that correct?\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": "7730",
"date": "24 Jan 2022",
"name": "Johny Pambabay",
"role": "Author Response",
"response": "Dear Reviewer, We would like to thank the reviewer for careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which help to improve the quality of this manuscript. Please see below, for a point-by-point response to the reviewers’ comments and concerns. Reviewers' Comments to the Authors: The only correction or clarification to be made by the authors is as follows: This article presents multivariate methods (principal co-ordinates analysis (PCoA) and Biplot), but on page 5 in the section of methods the author mention Principal components analysis (PCA), is that correct? Author response: Thank you for pointing this out. The reviewer is correct. The correct term is principal co-ordinate analysis. This will be corrected in the article. Thank you for your attention. Best regards, Johny Pambaby"
}
]
},
{
"id": "118444",
"date": "24 Jan 2022",
"name": "N. Sofía Huerta-Pacheco",
"expertise": [
"Reviewer Expertise Computational Statistics",
"Multivariate Statistics",
"Statistics Education",
"Forensic Science",
"and Affective Computing"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article describes the behavior and distribution of the crimes presented during a period in Mexico City, which showed findings that allow the identification of the areas with the highest incidence of crime, as well as the temporality in which they happen. Therefore, it presents and identifies multivariate patterns of crimes in Mexico as mentioned in the title.\nI suggest that your manuscript should undergo extensive English revisions. The article does not present a common thread that guides the reader. It is necessary to complement the article with updated information related to reports made, for example, the Observatory of Mexico City and Data Civica reports. Some figures and tables have errors. If the abbreviations were already explained in Table 1, it is not required describing them in the text. I recommend omitting the days-of-the-week variable in Figure 4 since it presents an independent behavior compared to the other variables and affects the patterns of association. I advise using the Moran index to see the homogeneity of the evaluated sites. In the conclusions, it is not necessary to emphasize where the information is.\nReviewer Questions\n\nIs the work clearly and accurately presented and does it cite the current literature? The work lacks up-to-date information reported by official sources.\n\nIs the study design appropriate and does the work have academic merit? The design is adequate; however, when presenting the descriptive results of the proportionality of the crimes, it loses the focus in trying to describe them all. Besides, when the information is concluded, it becomes insufficient.\n\nAre sufficient details of methods and analysis provided to allow replication by others? The methods present sufficient description that can confuse the reader, hence I recommend making a description to make it more succinct.\n\nIf applicable, is the statistical analysis and its interpretation appropriate? The proposed methods are correct; however, the level of variability of representation in two factors are not described as well as the level of contribution of the selected variables.\n\nAre all the source data underlying the results available to ensure full reproducibility? The original data is shared. However, the database is missing a description of the variables as well as the filtered base of the variables, since of the 115,209 data, at least 4,280 have no geographic information to classify them within some delegation, such as the description of the process in Figure 1.\n\nAre the conclusions drawn adequately supported by the results? I believe that there is information that should not be in the conclusions, and there is a lack of further explanation of the most outstanding findings, for example, the patterns of crime schedules.\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? No",
"responses": []
},
{
"id": "118439",
"date": "22 Feb 2022",
"name": "José Luis Vicente Villardón",
"expertise": [
"Reviewer Expertise My area of research is multivariate statistics",
"especially biplots."
],
"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 biplot references are not adequate. Gabriel and Odoroff (1990) present the biplot in medical studies, but does not use Principal Coordinates. Gower (1966) uses principal coordinates, but not biplots. Both concepts together are presented by Gower in different papers, but a summary of all can be found in Gower & Hand (1995). This would be a much better citation for the joint use of principal coordinates and biplots.\nThe so called \"category level points\" are not defined in Pambabay-Calero et al. (2018). They use a biplot based on principal components for frequency data. Category level points refer to a different concept that can be found also in Gower and Hand (1995), and is related to a modified version of Multiple Correspondence analysis. The references of Kruskal(1964a, 1964b) do not describe PCoA (principal co-ordinates analysis) nor its relation to a biplot, rather describe Multidimensional Scaling that, although is a vary close technique, is not the same as PCoA. Again, the right reference is Gower and Hand (1995).\nThe initial matrix for the analysis is not clearly described in the paper. What does the matrix have in its rows and columns? The locations? The times? The crimes? Is it a frequencies matrix? Is it an indicator matrix? From the graphs it is not possible to infer the shape of the initial data introduced in the algorithm. The exact form of the input data matrix should be described clearly, (what are the rows and the columns?).\nThe description of the principal coordinates algorithm is confusing. First the inner product B is obtained from the data matrix X and later from the dissimilarity matrix D. In any case, the procedure to calculate dissimilarities from the raw data should be specified.\nNo clear method for the calculation of the biplot is described. The relation among principal coordinates and biplots is not clearly described, so, there is not enough information to replicate the calculations and the results. If finally, the used method is a classical biplot, the references to PCoA are not justified. Classical biplots are related to PCoA of the Euclidean distance matrix, but that does not justify including that technique in the description.\nThe exact R packages used for the calculations should be reported. If the calculations where made using routines of the authors should also be reported. A package to construct biplots is MultBiplotR. With this package the authors can avoid all the problems described later and improve the representations.\nFigures 4 and 5 are not adequate. PCoA analysis is interpreted using Euclidean (Pythagorean) distances. For that interpretation to be possible, one unit in the scale of the X axis must be exactly the same as one unit in the Y axis. That is not the case in both figures.\nA biplot is a joint representation of the rows and columns of a data matrix, so figures 4 and 5 should be combined in a single plot or represented with the same scale. It is quite obvious that the scales of both plots are quite different, so the whole procedure should be redone.\nThe quality of the plot also needs to be improved, both figures are very low quality and figure 5 is even not complete.\nWith all the deficiencies in the representation of biplots, I cannot judge the accuracy of the results. If I understand correctly and the input matrix contains frequencies and a classical biplot has been used, the accuracy of the analysis is not clear.\nAs a summary, the description and application of the statistical methods must be significantly improved for the paper to be acceptable. Obviously, the results must be modified consequently if necessary.\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?\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/10-1299
|
https://f1000research.com/articles/10-1297/v1
|
20 Dec 21
|
{
"type": "Research Article",
"title": "Performance Analysis of Simulated Annealing and Genetic Algorithm on systems of linear equations",
"authors": [
"Md. Shabiul Islam",
"Most Tahamina Khatoon",
"Kazy Noor-e-Alam Siddiquee",
"Wong Hin Yong",
"Mohammad Nurul Huda",
"Most Tahamina Khatoon",
"Wong Hin Yong",
"Mohammad Nurul Huda"
],
"abstract": "Problem solving and modelling in traditional substitution methods at large scale for systems using sets of simultaneous equations is time consuming. For such large scale global-optimization problem, Simulated Annealing (SA) algorithm and Genetic Algorithm (GA) as meta-heuristics for random search technique perform faster. Therefore, this study applies the SA to solve the problem of linear equations and evaluates its performances against Genetic Algorithms (GAs), a population-based search meta-heuristic, which are widely used in Travelling Salesman problems (TSP), Noise reduction and many more. This paper presents comparison between performances of the SA and GA for solving real time scientific problems. The significance of this paper is to solve the certain real time systems with a set of simultaneous linear equations containing different unknown variable samples those were simulated in Matlab using two algorithms-SA and GA. In all of the experiments, the generated random initial solution sets and the random population of solution sets were used in the SA and GA respectively. The comparison and performances of the SA and GA were evaluated for the optimization to take place for providing sets of solutions on certain systems. The SA algorithm is superior to GA on the basis of experimentation done on the sets of simultaneous equations, with a lower fitness function evaluation count in MATLAB simulation. Since, complex non-linear systems of equations have not been the primary focus of this research, in future, performances of SA and GA using such equations will be addressed. Even though GA maintained a relatively lower number of average generations than SA, SA still managed to outperform GA with a reasonably lower fitness function evaluation count. Although SA sometimes converges slowly, still it is efficient for solving problems of simultaneous equations in this case. In terms of computational complexity, SA was far more superior to GAs.",
"keywords": [
"Optimization",
"Simulated Annealing",
"Simultaneous Equations",
"Genetic Algorithms"
],
"content": "Introduction\n\nThe Simulated Annealing (SA) algorithm is a well-known meta-heuristic for solving problems that require best or optimal results. This algorithm can easily be implemented using some programming language and as such it has gained wide acceptance in the arena of computational and scientific research over the past few decades.\n\nOn the other hand, in Science and Engineering, systems of equations or simultaneous equations involving unknown variables are applied to solve real-life problems through mathematical modelling, in solving simultaneous equations, the two most common methods are the Substitution and the Elimination method.1 In one way, Substitution works nicely, especially for a system of two equations with two variables. However, for larger cases, such as a system of three equations with three variables, the Substitution method can become a time-consuming process. On the contrary, the Elimination method can be an easier alternative to solving equations involving three equations with three variables. Still, with an increase in the number of equations and variables, it can become a difficult and lengthy process. Besides, a numerical method called the Gaussian Elimination method is not always capable of finding good quality solutions for complex systems of equations.2 Hence, to be able to solve simultaneous equations using the SA approach could make the process of finding possible solution sets much easier, faster, and convenient.\n\nThe purpose of this research is to study the performances of the SA algorithm while comparing it with Genetic Algorithms (GAs), in solving simultaneous linear equations.\n\nGenetic Algorithms (GAs) have been used to solve simultaneous equations in the past. Abiodun et al.3 had implemented a GA to solve simultaneous linear equations. They experimented with seven different systems of equations and have performed a comparative analysis of their work with Gaussian Elimination method. They were successful in solving the equations using GA. In some cases, GA was able to give the best or exact solutions, which was not possible with the Gaussian Elimination method. Besides, their GA was able to find other combinations of solution sets which again was not possible with the existing conventional methods like Substitution, Elimination etc. Their work indicated the fact that GA was superior in its performances against the existing conventional methods of solving simultaneous equations.\n\nSimulated Annealing (SA) is an approach to solving optimization problems introduced by Kirkpatrick et al.4 where it uses the property of randomization in its search operations. The idea of the SA algorithm comes from metallurgy where it mimics the metal’s re-crystallization in the process of slow cooling of metal which is termed annealing.4\n\nIn the SA simulation,4 initially, the system undergoing optimization is melted at a high temperature. Next, the temperature is decreased slowly to freeze the system. This continues until no further change is possible. The SA algorithm has the capability to escape from local minima by accepting or rejecting new solution candidates based on a probability function.\n\nThe basic SA algorithm4 has the following procedure:\n\n1. T0 is the initial temperature that needs to be specified before the initialization of the solution candidate\n\n2. E is the fitness of the candidate that needs to be evaluated\n\n3. Next, the candidate has to be moved to a neighboring solution randomly\n\n4. E′ is the new solution whose fitness needs to be evaluated\n\n5. In case of E′ ≤ E, the new solution is accepted\n\n6. Whereas, in case of E′ > E, the new solution is accepted based on acceptance probability P, as shown in (1) below\n\n7. T stands for temperature that needs to be decreased.\n\n8. The SA search will stop if T is close to zero. Otherwise, it will go back to step 2\n\nThe temperature is regulated by the following:\n\nIn equation (2), k is the number of iterations. The symbol λ represents a coefficient that is used to adjust the cooling schedule by modification. The advantage of the SA approach is that it can obtain the global optimum with a greater probability, however, it requires many iterations to converge to a solution.\n\nSome recent applications of SA are discussed below.\n\nJayabalan et al.5 have proposed two modified versions of SAs to solve a scheduling problem known as permutation flowshop.\n\nIn another work, by Cunha and Marques,6 they have developed a trajectory-based SA with newer versions of reannealing and generation techniques that enable better convergence for producing solutions involving diversity and uniformity.\n\nIn a recent study,7 an approach called mixed-integer programming is discussed with SA proposed as a solution.\n\nOdziemczyk8 has introduced a procedure to solve a three-dimensional coordinate transformation problem using a variant of the SA technique.\n\nGrabusts et al.9 have experimented with the SA method and Travelling Salesman Problems (TSP) to find the shortest routes between destinations. Their study discussed applications of mathematical models that could be utilized to solve real-life problems.\n\nGallo and Capozzi10 have used SA to solve a scheduling problem that involves several key parameters like tempering, freezing etc. In one study,11 the authors have used a modified SA procedure to solve a problem related to sample allocation.\n\nIn both studies by A. A. N. P. Redi,12,13 SA algorithms have been applied in routing problems. In the first study,12 the objective was to find minimum routes that require less transportation time whereas, in the second study,13 the research aimed to reduce the transportation expenses.\n\nIn a most recent study in Engineering optimization, Meng14 tried to discover new parameters pertaining to the creative and cultural domain of product design to improve the performance of the SA algorithm.\n\nManaging tasks in cloud computing environment is huge and daunting and it requires smart handling. Therefore, the study by Fakhrosadat Fanian et al.,15 has contributed towards a better way of managing the scheduling of tasks by developing a new algorithmic approach that takes its inspiration from Firefly and SA algorithms.\n\nGripon, V et al.16 conducted certain experiments on training weights, which were discrete in nature, using a combination of traditional SA and ideas taken from statistical physics.\n\nP. Aravind et al.17 have used a heuristic method based on SA to overcome the problem of allocating switches within a short time for various networks. Their model was able to solve the problem within a reasonable amount of time for varied network sizes.\n\nAvinash C. Pandey and Dharmveer S. Rajpoot18 have focused on getting accurate results in the classification of features by combining the techniques of SA and grey wolf optimization.\n\nJie Zhou et al.19 have introduced an efficient way to increase the life span of largescale wireless sensor networks by using a special version of SA called “Elite Adaptive Simulated Annealing Algorithm (EASA)”.\n\nCzerniachowska, K et al.20 have addressed an interesting problem of arranging products on shelves which can be a strenuous task involving retailing decisions. Therefore, they have applied the SA procedure to handle the effective decision making of shelf allocation of products on symmetrical planograms.\n\nIn the area of industrial cutting, one study has investigated a problem called multi-objective optimization for irregular objects,21 in the field of processing aquatic products, and have developed a SA technique for the problem of squid cutting.\n\n\nMethods\n\nIn this study, both SA and GA have been implemented in MATLAB (Version: R2017a, RRID: SCR_001622) based on the setup of two algorithms stated in Table 1 and Table 2. MATLAB is software that provides functionality to implement algorithms, analyze data, or create models.\n\nSimultaneous equations, in Mathematics, play a very important role in modeling real-life problems. These comprise a set of equations, which is finite in nature and should meet at a common point in space.22 These equations should have functions of at least two variables and can either have a linear or a non-linear characteristic.\n\nAccording to Gilbert,23 a system of simultaneous equations, linear in nature, can be written in the following manner:\n\nThis equation can be represented using a matrix-vector as follows:\n\nIn this expression, unknown variables are contained in a vector x. The number of unknown variables is represented by N, and constants are represented by a, in a coefficient matrix represented by A.\n\nIn this study, both SA and GA have been implemented to find the values of unknowns in the equations.\n\nThe data is randomly generated to represent each unknown variable in a system of simultaneous equations. The generated data comprises each candidate solution set in SA and each chromosome in GA. In SA, a single vector of values or a solution set is initially generated, while in a GA, a population of 100 chromosomes is initially generated. In evaluating the fitness of each solution set in SA or a chromosome in GA, the randomly generated vector of values is used to evaluate the equation on the left-hand side (LHS). Next, the values of LHS are checked with the values on the right-hand side (RHS) to see if they are equal. If the evaluated value/values of equation/equations on the LHS are equal to the given value/values on the RHS of the equation/equations, then the solution set/chromosome of the unknowns is considered to be valid or fit to a system of equations.\n\nIn order to evaluate the fitness of each solution set in SA or a chromosome in GA, an arbitrary value of 3000 is taken as the start fitness value. For each equation or a system of equations, the absolute value of the difference of the LHS and the RHS is taken. Next, it is subtracted from the start fitness value of 3000, i.e.,\n\nIf the difference is equal to 0, the fitness value remains unchanged (i.e., 3000), otherwise, the fitness decreases. To calculate the energy of each solution set in SA, the fitness value of each solution set is subtracted from this arbitrary value (i.e., 3000), since fitness and energy are opposite to each other in the case of SA. This method of converting fitness to energy using the subtraction method resembles a flip flop operation.\n\n\nResults\n\nTable 3 above presents the results of SA, solving simultaneous equations. For this study, 10 different systems of equations, involving two, three and four unknown variables, were selected. Each experiment was performed 15 times, to record the average performance of SA. As can be seen in Table 3, for the first three systems of equations, involving two variables (Experiment number (No.) 1, 2 and 3), SA was able to give its best performance by solving them within a minimum of 3, 2 and 3 iterations each, while keeping the maximum average at 73 (Experiment No. 3). Table 1 and Table 2 below show the parameter setup for SA and GA, respectively.\n\nAgain, with equations involving three variables, the algorithm performed relatively well, by solving them within as few as 5 minimum iterations and 57, 80 and 83 iterations on average, (Experiment No. 4, 5 and 6). However, soon after that, the average number of iterations kept increasing, reaching a maximum of 176 iterations (Experiment No. 9). This increasing rate is perhaps an indication of the pattern complexity of solution sets (usually having a combination of both positive and negative numbers).\n\nAlso, it is interesting to note that, in experiment No. 8, SA was able to find three different sets of solutions, therefore, making it an efficient method over the other traditional techniques like substitution and elimination, as discussed earlier. While, in experiment No. 10, involving 4 variables, there was a sudden but usual increase in the minimum number of iterations, reaching a maximum of 61 iterations. However, in the long run, SA managed to keep its pace by maintaining a standard average of 150 iterations, relatively lower than in experiment No. 9.\n\nOverall, the SA algorithm was successful in solving the selected systems of equations within a reasonable number of iterations, maintaining a reasonable average of 176 iterations and 176 times fitness evaluation count. Figures 1–10 gives a glimpse of the performances of the SA algorithm implemented in MATLAB software, showing the various energy levels at each iteration count, until reaching a level of 0 at the target iteration, to find the expected solutions.\n\nTable 4 presents the results of GA solving simultaneous equations. In order to evaluate the performances of SA against GA, the same set of equations from SA were tested with GA. Each experiment was performed 15 times just like in SA.\n\nIn the first three experiments (Experiment No. 1, 2 and 3), GA was successful in solving the equations within an average of 2 generations. However, there was a sudden increase in the average no. of generations to 35 in experiment 4 with equations involving 3 variables. Next, in the following experiments from 5 through 8, there was a gradual decline in the number of average generations (i.e., 17, 12, 9 and 3, respectively), indicating the improved performance of the algorithm. In experiment 9, there was a dramatic increase in the average no. of generations reaching a maximum of 196. It is important to note that this sudden increase in the number of generations is consistent with the same experiment performed with SA earlier, where the average no. of iterations reached a maximum of 176 from 120. Perhaps, this increase is an indication of the pattern complexity in solution sets (usually having a combination of both positive and negative numbers), just like in the case of SA. In all the experiments from 1 to 9, the algorithm was able to find solutions within a minimum of 1 or 2 generations, until in experiment 10 (involving equations with 4 unknowns) there was a significant rise in the number of minimum generations to 8 and number of average generations to 50 due to the increase in problem size. However, the algorithm managed to maintain a relatively much lower number of average generations as compared to 196 in experiment 9 which is again consistent with the SA results shown earlier. GA was also able to find three different sets of solutions in experiment 8 just like SA, thus making both the optimization techniques in general, more efficient over the traditional methods like substitution and elimination, as mentioned earlier.\n\nEven though GA was able to solve all the equations just like SA, within a maximum average of 196 generations, its comparison with SA does make a huge difference since the maximum average number of iterations for SA stand at 176, which is lesser than in GA. Moreover, in SA, a single iteration means just 1 solution set, whereas, in GA, a single generation means a whole population of 100 chromosomes or solution sets (taken for this study). Therefore, the average fitness function evaluation for each solution set in the case of SA stands at 176 times, while in GA it stands at 196 × 100 = 19600 times, where the fitness evaluation takes place for the entire population of chromosomes in each generation, thus making it computationally expensive unlike in SA where the fitness evaluation takes place for just one solution set at each iteration.\n\nFigures 11-14 give a glimpse of the performances of the GA algorithm, implemented in MATLAB software, showing the maximum and the average population fitness of each generation until it reaches a maximum fitness of 3000 (a defined arbitrary fitness value) at the target generation and finds the expected solution sets.\n\n\nDiscussion\n\nThis research successfully applied Simulated Annealing (SA) algorithm and evaluated its performances against Genetic Algorithms (GAs). During this experimental study, the 10 different systems of simultaneous linear equations involving 2, 3 and 4 variables were solved.\n\nIn all the experiments, an initial solution set or a population of solution sets were randomly generated in both the SA and the GA, for the optimization to take place.\n\nIn the case of SA, the linear cooling schedule was used to control the temperature. The linear cooling schedule was effective in successfully finding all the solutions. Further, slow cooling by adding a constant (C = 50 and C = 100) was also tried in some cases but that did not make a big difference in the number of iterations to find solutions.\n\nIn the case of GA, a population size of 100, a reproduction rate of 60%, a crossover of 30% and elitism of 10% were used. The mutation rate was kept at 0.1.\n\nDuring the experimentation phase, the following observations were made:\n\n• While solving simultaneous equations, both SA and GA were equally able to solve them and resulted in more than one set of linear solutions for respective systems of those equations. For instance, in experiment 8 (Table 3 and Table 4), for both SA and GA, there have been observed three different sets of perfect solutions, which were a perfect fit on those equations. Thus, indicating the optimization technique to be efficient over the other conventional methods like the Gaussian Elimination Method etc.\n\n• Even though GA maintained a relatively lower number of average generations than SA, SA still managed to outperform GA with a reasonably lower fitness function evaluation count and thereby proved to be far more computationally efficient than GA.\n\n• Even though SA converges slowly sometimes, it can still be regarded as an efficient technique for solving problems that require optimization.\n\n• In terms of computational complexity, the SA algorithm proved to be far more superior to GAs.\n\n\nConclusions\n\nThis study evaluated the performances of the Simulated Annealing (SA) algorithm over Genetic algorithms (GAs) in solving simultaneous linear equations.\n\nThe SA algorithm was applied to solve simultaneous linear equations and evaluated its performances against GAs.\n\nThe limitation of this paper is that the problem of the real-time system has been solved with a set of only linear equations instead of both linear and non-linear equations.\n\nHowever, in future, the focus of this research experiment with SA will be on providing solutions with non-linear systems of equations. Furthermore, as part of future work, Harmony Search24 as a recent optimization technique can be used to solve systems of equations based on music improvisation.\n\n\nData availability\n\nNo data are associated with this article\n\n\nEthical approval and consent\n\nNo humans or animals were included in this study.\n\n\nAuthor contribution\n\nMd. Shabiul Islam: Conceptualization, Supervision, Writing-Review & Editing\n\nMost Tahamina Khatoon: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing-Original Draft\n\nKazy Noor-e-Alam Siddiquee: Conceptualization, Formal Analysis, Methodology, Project Administration, Writing-Original Draft Preparation, Writing-Review & Editing\n\nWong Hin Yong: Writing-Review & Editing\n\nMohammad Nurul Huda: Supervision, Writing-Review & Editing",
"appendix": "References\n\nUgboduma, Samuel S: Students' Preference of Method of Solving Simultaneous Equations. Glob. J. Educ. Res. 2012; 11(2) Publisher Full Text\n\nGrcar JF: Mathematicians of Gaussian Elimination. Notice of the AMS. 2011; 58(6) https://www.ams.org/notices/201106/rtx110600782p.pdf\n\nAbiodun IM, Olawale LN, Adebowale AP: The Effectiveness of Genetic Algorithm in Solving Simultaneous Equations. Int. J. Comput. Appl. 2011; 14(8): 38–41. Publisher Full Text\n\nKirkpatrick S, Gelatt JD, Vecchi MP: Optimization by simulated annealing. Science. 1983; 220(4598): 671–680. Publisher Full Text\n\nJayabalan K, Pugazhendhi S, Rajendran C, et al.: Simulated annealing algorithms to minimise the completion time variance of jobs in permutation flowshops. Int. J. Ind. Syst. Eng. 2019; 31: 425. Publisher Full Text\n\nCunha M, Marques J: A New Multiobjective Simulated Annealing Algorithm—MOSA-GR: Application to the optimal design of water distribution networks. Water Resour. Res. 2020; 56: e2019WR025852. Wiley Online Library ADS Web of Science®Google Scholar. Publisher Full Text\n\nYang W, Cheng W: A Mathematical Model and a Simulated Annealing Algorithm for Balancing Multi-manned Assembly Line Problem with Sequence-Dependent Setup Time. Math. Probl. Eng. 2020; 2020: 1–16. Article ID 8510253.Publisher Full Text\n\nOdziemczyk W: Application of Simulated Annealing Algorithm for 3D Coordinate Transformation Problem Solution. Open Geosci. 2020; 12: 491–502. Publisher Full Text\n\nGrabusts P, Musatovs J, Golenkov V: The application of simulated annealing method for optimal route detection between objects. Procedia Comput. Sci. 2019; 149: 95–101. 18770509. Publisher Full Text Reference Source\n\nGallo C, Capozzi V: A Simulated Annealing Algorithm for Scheduling Problems. J. Appl. Math. Phys. 2019; 07: 2579–2594. Publisher Full Text\n\nO'Luing M, Prestwich S, ArmaganTarim S: A Simulated Annealing Algorithm for Joint Stratification and Sample Allocation Designs. arXiv e-prints. 2020.\n\nRedi AANP: Simulated annealing algorithm for solving the capacitated vehicle routing problem: a case study of pharmaceutical distribution. J. Sist. Manaj. Ind. Jul. 2020; 4(1): 41–49. Publisher Full Text\n\nRedi AANP, Jewpanya P, Kurniawan AC, et al.: A Simulated Annealing Algorithm for Solving Two-Echelon Vehicle Routing Problem with Locker Facilities. Algorithms. Sep. 2020; 13(9): 218. Publisher Full Text\n\nMeng X: Optimization of Cultural and Creative Product Design Based on Simulated Annealing Algorithm. Complexity. 2021; 2021: 1–10. Article ID 5538251. Publisher Full Text\n\nFanian F, Bardsiri VK, Shokouhifar M: A New Task Scheduling Algorithm using Firefly and Simulated Annealing Algorithms in Cloud Computing. Int. J. Adv. Comput. Sci. Appl. 2018; 9(2). Publisher Full Text\n\nGripon V, Löwe M, Vermet F: Some Remarks on Replicated Simulated Annealing. J. Stat. Phys. 2021; 182: 51. Publisher Full Text\n\nAravind P, Saradhi Varma GP, Prasad Reddy PVGD: Simulated annealing based optimal controller placement in software defined networks with capacity constraint and failure awareness. J. King Saud Univ. - Comput. Inf. Sci. 2021; 1319-1578. Publisher Full Text\n\nPandey AC, Rajpoot DS: Feature Selection Method Based on Grey Wolf Optimization and Simulated Annealing. Recent Adv. Comput. Sci. Commun. 2021; 14(2): 635–646. Publisher Full Text ,\n\nZhou J, Jia W, Liu M, Xu M: Elite Adaptive Simulated Annealing Algorithm for Maximizing the Lifespan in LSWSNs. J. Sensors. 2021; 2021: 11. Article ID 9915133. Publisher Full Text\n\nCzerniachowska K, Hernes M: Simulated Annealing Hyper-Heuristic for a Shelf Space Allocation on Symmetrical Planograms Problem. Symmetry. 2021; 13: 1182. Publisher Full Text\n\nLiu S, Wang H, Cai Y: Research on Fish Slicing Method Based on Simulated Annealing Algorithm. Appl. Sci. 2021; 11: 6503. Publisher Full Text\n\nNordin N, Tengah K, Shahrill M, Tan A, Leong E: Using Visual Representations as an Alternative in Teaching Simultaneous Equations.2017. Publisher Full Text\n\nGilbert S: Linear Algebra and Its Applications. Pacific Grove: Brooks Cole; 2007.\n\nGeem Z, Kim J: A new heuristic optimization algorithm: Harmony search. Simulation. 2001; 76(2): 60–68. Publisher Full Text"
}
|
[
{
"id": "116271",
"date": "14 Jan 2022",
"name": "Aloke Kumar Saha",
"expertise": [
"Reviewer Expertise Algorithms",
"Machine Learning",
"Natural Language Processing",
"Deep Learning."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a good work. However there are some observations from my end:\n1. Authors mentioned that no data are associated with this article, but they provided some examples. I think the number of examples should be increased.\n2. Authors did not mentioned the number of variables for solving the problems. They should mention if there are any restrictions about the number of variables.\n3. This is highly mathematical, but the problem of the real-time system should be developed with a set of linear and non-linear equations.\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": "116261",
"date": "14 Jan 2022",
"name": "Andranik S. Akopov",
"expertise": [
"Reviewer Expertise Genetic Algorithms",
"Neural Networks",
"and Deep Learning",
"Fuzzy Logic",
"Artificial Intelligence",
"Multiagent systems"
],
"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 problem statement described in the submitted paper does not make sense. Genetic Algorithms are applied to solve more complex optimization problems (e.g., non-convex, multiobjective optimization, etc.). Thus, the proposed method looks like an application of complex heuristic algorithms to solve very simple optimization problems related to the systems of linear equations. The second important concern is the examined algorithms (i.e., GA and Simulated Annealing) are standard and do not have any significant improvements. I did not find any comparisons of studied algorithms with other GAs (e.g., RCGAs, parallel GAs, Hybrid GAs) in performance. Moreover, the detailed description of used methods (i.e., SA and GA) with the use of pseudocode is absent. I found the reference to the MATLAB framework only without any technical details of the used methods and procedures. That also confirms the examined algorithms are standard and don't have any improvements. Based on these facts, I cannot recommend this article for indexing.\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? 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": "7706",
"date": "17 Jan 2022",
"name": "KAZY NOOR E ALAM SIDDIQUEE",
"role": "Author Response",
"response": "Dear Reviewer Thank you very much for your formatted review. The work is primarily focusing on linear systems equation prioritizing 10 equations as a sample. Other variants of SA are our future milestones to go for experimentation. With regards, Kazy"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1297
|
https://f1000research.com/articles/10-890/v1
|
06 Sep 21
|
{
"type": "Research Article",
"title": "Playing Edcraft at Home: Gamified Online Learning for Recycling Intention during Lockdown",
"authors": [
"Kin Meng Cheng",
"Ah Choo Koo",
"Junita Shariza Mohd Nasir",
"Shen Yuong Wong"
],
"abstract": "Background: Recycling is a way to sustain ecosystems. There are substantial studies on recycling intention due to the continual growth of unethical and unsustainable waste disposal. Creative approaches to recycling awareness activities should be made to fulfil youths’ increasing interest in and demand for recycling. The main objective of this study is to explore the factors related to youths’ recycling intentions after experiencing a gamified online recycling learning activity, Edcraft Gamified Learning (EGL). Gamified recycling education is believed to be a practical and engaging approach for youths. Methods: 100 students participated in EGL, consisting of two levels of plastic crafting and recycling activities. They experienced online EGL at home between May and September in 2020, during the COVID-19 pandemic total lockdown in Malaysia, namely, Movement Control Order (MCO). 29 participants were selected to participate in five focus group discussions (FGDs) with five to eight participants per session to explore their opinions towards gamified learning, motivation and recycling intention. Results: This paper reports the findings of the FGDs. A codebook was developed based on the codes from the FGD feedback. The codes were rated by two raters, followed by an assessment of inter-rater reliability and thematic analysis. The findings emerged and were confirmed with four themes as factors that influence recycling intention. They are gameful experience, social influence, intrinsic motivation, and extrinsic motivation. Conclusion: The dependent variable, recycling intention, was connected to the four themes to verify the conceptual framework. One limitation of the study was the design of the EGL activity, which was only carried out over two days with two levels of gamified recycling education, as students had concurrent academic online classes during that period.",
"keywords": [
"Recycling intention",
"Gamified learning",
"Youth",
"Digital natives",
"Qualitative",
"Focus group discussion",
"Edcraft",
"Inter-rater reliability"
],
"content": "1 Introduction\n\nMost countries have long ago adopted recycling to preserve the environment’s health.1 Recycling behaviour has promoted a positive attitude towards the environment within society. Around the world, municipal waste production correlates with a country’s economic growth. Statistics show that pro-environmental behaviour, awareness, and intentions are the most direct measures for coping with daily household waste production. Nonetheless, plastic packaging increased 53% internationally during the lockdown in the pandemic situation between March and June 2020.2\n\nA study conducted in 2017 and 2018 shows a negative attitude towards recycling in many countries, claiming that recycling education and infrastructure are insufficient.3,4 However, the negative attitude had caused severe destruction to the environment, as they are often more reactive and ‘always forgot’ or ‘do not care’ about the act of recycling when there is no support from recycling infrastructure, facilities or programmes.5\n\nThis research aims to examine the factors that influence youths’ recycling intention after experiencing a gamified online learning activity, Edcraft Gamified Learning (EGL), and to explore the effectiveness of gamified learning about recycling within a research framework.6\n\n\n2 Literature review\n\nYouths between the ages of 15 and 24 comprise 17% of the world’s population, and they are the critical agents of change for the future, especially on climate change.7 Youth has been understood as the responsible group to bring the benefits of society in the world, taking its place in attitudes, behaviours, knowledge and skills.6 Greta Thunberg, a young climate and environmental activist, continues to lead, promote and motivate young people’s awareness and behavioural changes towards pro-environmental actions. She encourages her followers to use digital platforms for pro-environmental awareness and actions.8,9 Thunberg’s actions have also influenced some Malaysian youths to take climate action locally, such as that taken by Klima Action Malaysia (KAMY).10 The youth-led green and climate movements have created a new revolution for positive environmental change, as evidenced by their influence and leadership on social media.\n\n2.1.1 Youths as digital activists for positive change\n\nYouth populations are exposed to vast amounts of information, and multimedia and social media are recognised by these “digital natives”.11 The long hours youth spent online surfing the internet, socialising and playing video games in the virtual world during lockdowns due to the pandemic has increased tremendously. The long period spent by the youths in the virtual world has created an effective platform to influence their peers through video games and social media.\n\nStudies have shown that youths opt to spend time playing video games online to avoid adverse psychological effects while confined at home during the pandemic.12,13 Young people should be exposed to positive activities to create an impact for any form of good cause, including pro-environmental initiatives. The initiatives can be done online, as demonstrated by youth leaders such as Thunberg and KAMY.\n\nWaste separation and recycling are methods to curb problems associated with environmental hazards. Recycling is also a way to save economic and environmental resources. Hence, the importance of recycling behaviour has been studied, and it has been found that one of the most critical factors for achieving the effectiveness of recycling programmes is public participation,3 which was studied by this research as people’s intention to participate in recycling. Recycling is seen as problematic by some, who may perceive it as time-consuming and something that requires considerable effort.14,15\n\nGermany and Sweden are among the countries that were positively impacted by their recycling programme in educating and engaging the people in waste separation and reached 90% of active participants in waste separation activity.16,17 Gamified learning is considered to engage people in recycling, and Table 1, below, shows four different gamified environmental education programmes.\n\nFrom the findings in Table 1, the common traits of gamified environmental awareness learning are that gamification can potentially influence the adoption of a positive recycling intention.\n\nRecycling intention\n\nSome people perceive recycling as a time-consuming activity. This study will make use of gamification to engage the youth involvement in recycling, and change their “always forgot” and “do not care” attitude towards recycling intention.5\n\nIn Figure 1, the study has conceptualised a framework of recycling intention initiated by gamified learning. It is conceptualised that the youths’ motivation is from family and friends, and that gamification plays a part in avoiding the negative psychological effects that may occur during times when people’s movement is restricted while also helping manage the bulk of household waste.\n\nThere are two research questions (RQ) from the research:\n\n1) How effective is the online gamified recycling activity towards youths’ recycling intention?\n\n2) What are the factors of recycling intention that leads to the research conceptual framework?\n\n\n3 Methods\n\nThe qualitative study relates to the two-level online gamified recycle crafting activity, namely Edcraft Gamified Learning (EGL) activity during the COVID-19 pandemic lockdown between May and September 2020. EGL is an activity where participants were required to undergo two days, two levels and each level one craft activity. Participants were also given a day to work on each of their craft freely and creatively.\n\nThis activity involved 100 youths from three institutions, one high school and two colleges in Selangor, Malaysia, who were 16–23 years old and staying at home due to the pandemic. Participants were recruited from their schools and collegesthrough the activity recruitment poster and “Word-of-Mouth”, with the help of the teachers and lecturers.\n\nThey provided written consent to participate on the day of the activity and were informed that the data would be for research and publication use. After experiencing two-level EGL, 29 students were purposively selected as FGD participants. Participants with excellent achievement, commitment and attention to the activity were selected for the FGD.\n\nRecordings were made of each of the five online FGD sessions. Each session lasted for 50–70 minutes, and could be listened to for a second time to identify recurring data patterns. Participants were given instructions beforehand and were informed several days before the FGD. The researcher was also given consent by each of the participants to conduct the FGD sessions. Recorded sessions were transcribed from audio to text. Later, the transcripts were coded and compiled into a codebook for inter-rater reliability assessment.\n\n3.1.1 Coding assessment\n\nInter-rater reliability assessment\n\nTo obtain code consensus from the raters, the degree of agreement scores, 0 and 1, were measured by two raters. Both raters were trained to perform their task by identifying the target behaviour from the transcripts.22 According to,23,24 the value of 0.78 in Table 2 shows the kappa statistics of agreement that were analysed by the IBM Statistical Package for Social Sciences Statistics (SPSS) Version 26 software (IBM SPSS Statistics, RRID:SCR_019096). An open source alternative to SPSS is GNU PSPP. The statistics show substantial or very good agreement relative to the kappa statistics.\n\na Not assuming the null hypothesis.\n\nb Using the asymptotic standard error assuming the null hypothesis.\n\nOnce the coding assessment had been done, the 37 codes were familiarised, then further sorted into 13 categories and organised as themes based on repeated patterns and similarities in their nature. Thematic analysis was used in the qualitative analysis of the FGDs to identify, organise, describe, and report themes for more trustworthy. Themes were reviewed for the second and third time to gain insightful and accurate findings that match the research questions.25\n\n\n4 Results and discussion\n\nFindings from the FGDs revealed four main themes, and these four themes are the independent variables or factors that influence the youths’ recycling intention. They are as follows:\n\n1) Engagement with the gamified recycling activity,\n\n2) Intrinsic motivation,\n\n3) Extrinsic motivation, and\n\n4) Social influence.\n\nRecycling intention is the dependent variable. All responses from the four themes were to answer RQ 1, explore the effectiveness of online gamified recycling activity that leads to recycling intention and verify the conceptual framework in Figure 1. The 13 categories were related to the participants’ responses, as shown in Appendix A.\n\n29 students from the FGDs shared their insights, responses, opinions and experiences online on how they acted towards the activity, the recycling issue in Malaysia, in FGDs during the COVID-19 pandemic.\n\nEach theme was listed in this section, and the categories were discussed based on the participants’ FGD responses. Insights from the interviews were highlighted to create a progressive construct on the conceptual framework to explore the ideas and meaning from the participants. All the verbatim were directly quoted from their original meaning.\n\n4.1.1 Engagement from gamified Learning activities\n\nWhen the researcher asked about their engagement on gamified learning activities, Participant P said it is crucial not to fall behind and feel ashamed. Therefore, they tend to work harder: “Yeah I think it is very important if not I will also would like you know so like I actually put more effort.” Participant R, too, was engaged because of their friend’s ranking and they valued the interaction between peers: “Your friend has a higher ranking and … work a little bit harder to get a higher rank...” Participant T stated that “We use game to compare...then it will have missions to work on, then it has the leaderboard from it, and reward, all has it in the Edcraft. I think this fulfills the standard of gameful.” Participant T had experienced video games and compared the fun of the gamified learning activity to a video game.\n\n4.1.2 Intrinsic motivation\n\nParticipant K made a strong statement about the accomplishment of the EGL activity: “Yes, I feel it gives me the sense of accomplishment … I keep on doing...about 6-7 hours until I upload the video … I feel the sense of accomplishment...” Several participants felt the happiness from accomplishment more than obtaining the physical reward. Recognition has intrinsically motivated the students, and they appreciate what they have earned through hard work. “I think rewards are important … certificate they will be useful … I think you can put it in your resume.” Additionally, enjoyment is part of the participants’ emotions. They immersed themselves in the activity and felt a sense of pleasure. Participant O was triggered by the activity and enjoyed the process of making a craft out of unused recyclable items: “After participated the Edcraft … it taught me that bottle can turn into other things...”\n\n4.1.3 Extrinsic motivation\n\nParticipants stayed motivated all the way to the end of the activity because they were promised a certification and prizes as rewards for completion. A reward is a form of extrinsic motivation as a temporary driver for them to recycle for participant J: “I am aiming for the certificate … the cert is very important...” Participant Q mentioned motivation from rewards: “I think after organising Edcraft, it will cultivate the awareness of recycling. Just like vase they need to create by themselves, need to spend money and expensive. If use plastic, it looks beautiful and quite practical as well.”. This response shows that the participant appreciates their crafting and building up their confidence to recycle.\n\n4.1.4 Social Influence\n\nParticipants are competitive when they are trying their best to earn a reward within a challenging environment among a group of friends. They influenced each other, and EGL has shown its social influence in competition: “I think it kind of affects in a positive way for youth … you will feel like want to do better than them.” Some participants take competition, points and rankings seriously: “I have some friend, first round only got 11 points then second round same points as me 41 points … they are so serious, persist and not giving up.”\n\n4.1.5 Recycling intention among youth\n\nParticipant A agreed that habit plays a role in recycling. “That is because they just do it all in habit … we do have like a monthly sort of activity in our community.” This clearly demonstrates that Participant A has done this for some time and is committed to the activity due to habit. Likewise, Participant D shows the expression of habit, saying, “every year always got talk about environment and the 3R so that’s how we all grew that habit of recycling …” There is a participant who believes that recycling is an activity that needs to be cultivated from an early age, following role models such as teachers, parents and friends. According to Participant F, “what motivates the young people to do recycling mostly comes from family. If your family practice then the children would probably just follows.” There are some participants who mentioned following teachers’ rules, being punished, recycling for the sake of rules or orders from elders: “teacher will punish the class which is not doing recycling … the person will receive punishment by sending to recycling center to wash recycling item.” Participant K loved the idea of an online EGL recycling activity: “I think after organizing Edcraft, it will cultivate the awareness of recycling … If use plastic, it looks beautiful and quite practical as well.” By having EGL, recycling awareness awakened participants’ thoughts about having fun recycling.\n\nFive topics from the FGD based on the codes were finalised into four themes:\n\n1) Gameful experience,\n\n2) Intrinsic motivation,\n\n3) Extrinsic motivation, and\n\n4) Social influence.\n\nThe four main themes are the main factors that influence recycling intention to address RQ 2.\n\nThe responses show that participants were engaged with the activity. They felt the fun of the video game-like experience and were socially influenced by competition among their friends to get into the action of recycling and recycling intention.\n\nThe collected data and themes were used to verify, enrich and create the “flow”, referring to the conceptual framework in Figure 1 and factors that influence recycling intention from RQ 1 to address RQ 2, as shown in Figure 2.\n\n\n5 Implications and conclusion\n\nYoung people are part of social change, and they bring an impact to the betterment of the environment through recycling activities. The incorporation of gamified learning for improving recycling intention can be brought about through social influence and intrinsic and extrinsic motivations. This study serves as a starting point for researchers to dig deeper into the elements that influence intention and behavioural change among youths. The method used in this study is FGDs. This research used inter-rater reliability on the coding agreement and thematic analysis to reduce ambiguities and develop quality themes and frameworks that lead to well-grounded gamified online recycling learning. However, recycling activity requires commitment, and the two-day, two-level activity represented a short time for attitude development. It is hoped that with the incorporation of gamified online learning, the impact of social influence on pro-environmental awareness and recycling, similar to the achievements of Greta Thunberg and KAMY, can spread to more young people around the world. Cultivation of recycling behaviour requires a longer-term gamified activity to effectively close the gap between fun learning and recycling intention.\n\n\nData availibility\n\nOpenDans: Online Gamified Learning: Focus Group Discussion Data set, May - August 2020. https://doi.org/10.17026/dans-xzu-as8s.26\n\nThis project contains the following underlying data:\n\n• Data file 1. (Cohen kappa reliability output in.spv format)\n\n• Data file 2 to 6. (Focus Group Discussion Transcription in pdf.)\n\n• Data file 7 to 10 (interrater reliability in.doc, .dat, .sav, and.sps format)\n\n• Data file 11 (invitation letter for interrater)\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\nEthical approval\n\nEthical approval (EA) number from Multimedia University (approved by secretariat of Research Ethics Committee): EA2642021.",
"appendix": "References\n\nVeizer J: Sedimentation in geologic history: Recycling vs. evolution or recycling with evolution. Contrib. to Mineral. Petrol. 1973; 38(4): 261–278. Publisher Full Text\n\nFilho WL, et al.: COVID-19 and waste production in households: A trend analysis. Sci. Total Environ. 2021; vol. 777. Publisher Full Text\n\nAlmasi A, et al.: Assessing the knowledge, attitude and practice of the kermanshahi women towards reducing, recycling and reusing of municipal solid waste. Resour. Conserv. Recycl. 2019; vol. 141, no. November 2018, pp. 329–338. Publisher Full Text\n\nYukalang N, Clarke B, Ross K: Barriers to effective municipal solid waste management in a rapidly urbanizing area in Thailand. Int. J. Environ. Res. Public Health . 2017; 14(9): 9–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumar D, Kumar SA: Why Don’t People Recycle-A Comparative Study Between The United States of America and India. Int. J. Soc. Sci. Econ. Res. 2018; (2): 6692–6712. Reference Source\n\nHo E, Clarke A, Dougherty I: Youth-led social change: Topics, engagement types, organizational types, strategies, and impacts. Futures . 2015; 67: 52–62. Publisher Full Text\n\nFernandez G, Thi TTM, Shaw R: Climate Change Education: Recent Trends and Future Prospects. In: Education for Sustainable Development and Disaster Risk Reduction. Shaw R, Oikawa Y, Eds. Tokyo: Springer Japan; 2014, pp. 53–74.\n\nFinnegan W: Environmental activism goes digital in lockdown – but could it change the movement for good?. The Conversation. 2020. (accessed 1st June, 2021). Reference Source\n\nGreta Thunberg: Who is she and what does she want?. BBC. 2020. (accessed 1st June, 2021).Reference Source\n\nRagunathan Y: Inspiring Stories from Malaysian Youth Leaders.2020. (accessed 4th June, 2021).Reference Source\n\nYang S, Lee JW, Kim HJ, et al.: Can an online educational game contribute to developing information literate citizens?. Comput. Educ. 2021; vol. 161, no. October 2020, p. 104057. Publisher Full Text\n\nWong HY, et al.: Relationships between severity of internet gaming disorder, severity of problematic social media use, sleep quality and psychological distress. Int. J. Environ. Res. Public Health. 2020; 17(6): 1–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrooks SK, et al.: The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020; 395(10227): 912–920. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang Z, Guo D, Wang X: Determinants of residents’ e-waste recycling behaviour intentions: Evidence from China. J. Clean. Prod. 2016; vol. 137, no. February 2009, pp. 850–860. Publisher Full Text\n\nStrydom WF: Barriers to household waste recycling: Empirical evidence from South Africa. Recycling. 2018; vol. 3, no. 3. Publisher Full Text\n\nStoeva K, Alriksson S: Influence of recycling programmes on waste separation behaviour. Waste Manag. 2017; 68: 732–741. PubMed Abstract | Publisher Full Text\n\nSchwarz-Herion O; Practical Action Nepal: A case study on successful municipal solid waste management in industrialized countries by the example of karlsruhe city, germany. J Eng. Ann. 2008; no. year, pp. 1–59. Reference Source\n\nMiralem Helmefalk JR: Make Waste Fun Again! A Gamification Approach to Recycling. Conf. Int. Conf. ArtsIT, Interactivity Game Creat. Int. Conf. Des. Learn. Innov. 2020; vol. 328 LNICST, no. July, pp. 785–787. Publisher Full Text\n\nLidia A: How to Encourage Recycling Behaviour? The Case of WasteApp: A Gamified Mobile Application.2018; pp. 1–20. Publisher Full Text\n\nBetaubun M, Nasrawati N: English for Specific Purpose: Revitalizing Climate Change Awareness Using Digital Literacy and Gamification for Engineering Faculty in Papua. J. Iqra’ Kaji. Ilmu Pendidik. 2020; vol. 5, no. 2, pp. 68–82. Publisher Full Text\n\nGibovic D, Bikfalvi A: Incentives for Plastic Recycling: How to Engage Citizens in Active Collection. Empirical Evidence from Spain. Recycling. 2021; 6(2): 29. Publisher Full Text\n\nPopping R: Introduction to Interrater Agreement for Nominal Data.2019. Publisher Full Text\n\nLandis JR, Koch GG: The Measurement of Observer Agreement for Categorical Data. Biometrics. Jan. 1977; 33(1): 159–174. PubMed Abstract | Publisher Full Text\n\nRegier DA, et al.: DSM-5 field trials in the United States and Canada, part II: Test-retest reliability of selected categorical diagnoses. Am. J. Psychiatry. 2013; 170(1): 59–70. PubMed Abstract | Publisher Full Text\n\nBraun V, Clarke V: Using thematic analysis in psychology. Qual. Res. Psychol. Jan. 2006; 3(2): 77–101. Publisher Full Text\n\nCheng KM: C (Multimedia University) (2020): Online Gamified Learning: Focus Group Discussion Data set, May - August 2020. DANS. Publisher Full Text"
}
|
[
{
"id": "93524",
"date": "09 Sep 2021",
"name": "Herdiyan Maulana",
"expertise": [
"Reviewer Expertise Thematic analysis study",
"Well-being",
"Online mental health services",
"well-being",
"social 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\nI appreciate the authors for bringing a very interesting yet important research theme into the table. The paper presented an insightful message about the potential uses of gamified based intervention to enhance youth recycling intention. However, there are number of concerns about the way in which the paper is presented. The following suggestions are intended to assist the authors in improving the quality of their paper.\nThe introduction need to be refined, there are numbers of unclear and inefficient sentences:\n1) \"Most countries have long ago adopted recycling to preserve the environment’s health.\" This sentence is ambiguous, what do the authors mean by the environment's health? This sentences also need for further grammar check.\n2) The sentence in paragraph 2 \"A study conducted in 2017 and 2018 shows a negative attitude towards recycling in many countries, claiming that recycling education and infrastructure are insufficient\". The authors indicated \"A study\" but the citation refers to two different studies. This sentence also not clear, what do the authors mean by \"a negative attitude?\" please clarifiy.\n\nTable 1. needs to be clarified. It may an idea to add study type, findings, and recommendations column for cited papers.\n\nI also notice that some papers included in Table 1. did not clearly state the effectiveness of gamified method as a potential way to enhance people's recycling intention. e.g. Study by Betaubun & Nasrawati (2020), which according to the author, can be used as a reference to show the use of gamified approach for enhance recycling intention, was as a cross-sectional study. To provide strong evidences for the potential used of gamification method to enhance recycling intention, I suggest the authors to cite an experiment based publications.\n\nAs this is a qualitative study, a research question addressing the effectiveness of the program might be problematic. Objective indicators and systematic measures should be applied to answer if the program is really effective. Rather than testing the effectiveness, this study may focus on describing subject's subjective experiences using the program, and how their experiences benefit for developing the program. Further, the author may describe in more detail about the game itself. Why and how the game is delivered, e.g., duration, elements, self-guided or full-guided, online/offline, and system requirements of the program.\n\nBraun & Clarke (2006) thematic analysis comprises series of steps when analyzing the qualitative transcriptions. The steps including how the authors develop low-order and high order themes. Please consider to explain the analysis steps in more detail.\n\nThe authors may need to explain in a bit more detail about the conceptual model (figure 2). How did the authors come up with this model? What thematic analysis results lead to this model?\n\nSuggestion to test the model using quantitative method should be added.\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": "7551",
"date": "20 Dec 2021",
"name": "kinmeng cheng",
"role": "Author Response",
"response": "Thank you so much for the review. I have made the changes accordingly based on the comments. 1) Unclear statements regarding to environment's health and sentence coherency have been changed and clarified. 2 and 3) Table has two new added columns on study type and recommendations. I have removed the study by Betaubun & Nasrawati (2020) and replaced it with a new empirical article \"Advocating recycling and encouraging environmentally friendly habits through gamification: An empirical investigation\" which provides stronger evidences for the effectiveness of gamification in recycling intention. 4) I have enriched the conclusion and discussion part to show how the EGL effectively improves youths' motivation to recycle. Social influence is emphasised in several sections of the paper. 5) 6 phases of thematic analysis have been added in 3.1 and leading each of the steps in the following sections to provide a clearer reading for the readers. 6) Additional explanation and improvement on the conceptual framework part. 7) Suggestions for future quantitative study have been added."
}
]
},
{
"id": "96007",
"date": "17 Nov 2021",
"name": "Ariffin Abdul Mutalib",
"expertise": [
"Reviewer Expertise Human-Computer 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\nIn general, the paper sounds like an empirical study, but the process does not sound technically sufficiently. Please consider the following to improve the paper:\nThe introduction can be better addressed by discussing the domain of study first, followed with the context of the study. The aim of the study should be stated in the section as well.\n\nThe literature review should also focus on the domain of study, showing the gap (that the study taps into).\n\nThe methods are too general and lack justification. Some parts need strong justifications, like sampling.\n\nThe results and discussion are too brief. Perhaps, you can focus on one factor and discuss more deeply.\n\nImplications should compare the findings in this paper with those previously found by others.\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\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7552",
"date": "20 Dec 2021",
"name": "kinmeng cheng",
"role": "Author Response",
"response": "I have strengthened the abstract, introduction and included gamified learning to guide the readers on domain of study. Literature has been enriched with gamified learning and recycling. Methods has been strengthened with a clearer explanation of the EGL activity and a new Figure 2 to show the flow of the data collection activity. Results and discussion has improved accordingly and social influence has been addressed, deeper meaning based on the results. Implications have shown that the research from table 1 can be a potential reference for future expansion of the study for quantitative research. The four themes have been further discussed in the conclusion and implication section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-890
|
https://f1000research.com/articles/9-832/v1
|
30 Jul 20
|
{
"type": "Software Tool Article",
"title": "KinderMiner Web: a simple web tool for ranking pairwise associations in biomedical applications",
"authors": [
"Finn Kuusisto",
"Daniel Ng",
"John Steill",
"Ian Ross",
"Miron Livny",
"James Thomson",
"David Page",
"Ron Stewart",
"Daniel Ng",
"John Steill",
"Ian Ross",
"Miron Livny",
"James Thomson",
"David Page",
"Ron Stewart"
],
"abstract": "Many important scientific discoveries require lengthy experimental processes of trial and error and could benefit from intelligent prioritization based on deep domain understanding. While exponential growth in the scientific literature makes it difficult to keep current in even a single domain, that same rapid growth in literature also presents an opportunity for automated extraction of knowledge via text mining. We have developed a web application implementation of the KinderMiner algorithm for proposing ranked associations between a list of target terms and a key phrase. Any key phrase and target term list can be used for biomedical inquiry. We built the web application around a text index derived from PubMed. It is the first publicly available implementation of the algorithm, is fast and easy to use, and includes an interactive analysis tool. The KinderMiner web application is a public resource offering scientists a cohesive summary of what is currently known about a particular topic within the literature, and helping them to prioritize experiments around that topic. It performs comparably or better to similar state-of-the-art text mining tools, is more flexible, and can be applied to any biomedical topic of interest. It is also continually improving with quarterly updates to the underlying text index and through response to suggestions from the community. The web application is available at https://www.kinderminer.org.",
"keywords": [
"Text mining",
"web application",
"KinderMiner"
],
"content": "Introduction\n\nMany important scientific discoveries are subject to lengthy processes of trial and error. Because the experimental search spaces are so large, intelligent prioritization of research directions is essential for reaching novel discoveries quickly, and this requires both extensive breadth and depth of domain expertise. However, exponential growth in the scientific literature1,2 presents a major challenge to remaining conversant with recent knowledge in any domain.\n\nTo facilitate rapid prioritization of experimental search, we thus present the first public web application implementation of the KinderMiner algorithm3, built upon a text index of abstracts from PubMed4. The KinderMiner algorithm is a simple text mining algorithm based on co-occurrence counting within a corpus of documents. It addresses the prioritization problem by filtering and ranking a list of target terms (e.g. transcription factors or drugs) by their association with a key phrase (e.g. “embryonic stem cell” or “hypoglycemia”). The output list provides researchers with an informed starting point for understanding the state of literature in their domain, and for prioritizing potential research directions, thereby accelerating the discovery process. While other tools provide similar functionality, we find that KinderMiner’s string matching approach is more flexible and performs comparably or better than existing state-of-the-art tools.\n\nOur web application implementation of KinderMiner improves on the original published algorithm in multiple ways. First, we have constructed our own local biomedical literature index backing the web application. This obviates the need for researchers to produce their own corpus of documents in order to use KinderMiner. Furthermore, providing a local text index speeds up query times, owing to the fact that we no longer need to send repeated queries to a remote web service over the internet. The local index also gives us complete control over data processing, allowing for greater extensibility. Second, providing a graphical user interface increases accessibility over a command-line tool, allowing non-technical users to get results without the bottleneck of relying on computational assistance. The interactive filtering tool also makes it easier for users to visually analyze their results rather than simply picking an arbitrary threshold. Finally, we intend to continually improve the tool by updating the text index quarterly, by adding enhancements, and by acting on feedback from the community. In summary, our application is fast, easy to use, and provides the first publicly available implementation of KinderMiner for all to freely use and to help improve through their feedback.\n\n\nMethods\n\nAs stated, our web application provides an off-the-shelf implementation of the KinderMiner algorithm built on a provided text corpus derived from PubMed. Here we first briefly describe the KinderMiner algorithm, implementation details of our web application, explain the user interface, and compare our web application results to other state-of-the-art tools on a cell reprogramming task.\n\nGiven a list of target terms and a key phrase of interest, KinderMiner filters and ranks the target terms by their association with the key phrase. It does this via simple string matching and co-occurrence counting within a given document corpus. For every target term in the given list, KinderMiner uses exact token matching to count 1) the number of documents in which the target term occurs, 2) the number of documents in which the key phrase occurs, and 3) the number of documents in which the target term and the key phrase both occur. With these counts, KinderMiner constructs a contingency table of document-level co-occurrence for every target term. KinderMiner then performs a one-sided Fisher’s exact test on every contingency table, and filters out terms that do not meet a specified threshold of co-occurrence significance. Finally, KinderMiner ranks the remaining terms by the ratio of documents containing both the term and key phrase, over the total of documents containing the term, thereby giving a proportion of term association with the key phrase. Figure 1 shows a visual representation of the algorithm steps with an example for a single target term. In the web application, the filtration step is controllable with the interactive analysis tool.\n\nThe original KinderMiner publication used Europe PubMed Central5 as the article corpus, but dependency on a remote third-party corpus would be slower and harder to maintain for our web application. Instead, we constructed a local text index from the National Library of Medicine’s “Annual Baseline” Dataset4, containing roughly 30 million abstracts, and updated quarterly by supplementing files from the “Daily Update Files” Dataset. We download all data in XML format. For every PubmedArticle element in the XML, we extract the contents of the PubDate and AbstractText fields. We process the PubDate field into a publication year based on the documentation guidelines and do no further processing on the AbstractText field. We then convert these fields into a JSON format for ingestion by Elasticsearch. Finally, we ingest the converted JSON records into an Elasticsearch index (version 2.4.6). Note that our corpus contains the entirety of the released PubMed citation records, which includes publication records from as far back as the 18th century all the way to the time of ingestion. The results presented here are based on the index built from an ingest of PubMed in June of 2020. The dataset contains 31,030,308 citation records, and we indexed the abstract text with Elasticsearch using the standard analyzer, which applies a grammar-based tokenizer and lowercase filter to the text.\n\nOur web application implements the KinderMiner algorithm built on this provided text index from PubMed. The web application is built with the Flask framework (version 1.0.2) using Python (version 3.7.2), and we use MariaDB (version 5.5.65) for the web application database. When a request is submitted through the application, it is added to the database on a first-come first-serve basis for analysis. Our analysis daemon then uses the Elasticsearch Query Domain Specific Language to construct each of the queries in JSON and stores the counts back in the database for user consumption. Once a request is complete, the results are viewable, filterable, and downloadable.\n\nFirst, users have the option of either creating an account with their email address or using the application as a guest. With an account, users have indefinite access to all of their previously submitted queries and results. Guests have access to all of the same tools and functionality, except that their query history is limited to their current browser session. The two pages where users will spend most of their time are the query submission page, and the results table for each query. The query submission page (see Figure 2) allows users to submit a single query for a list of target terms and key phrase. On this page, users can name the query for future reference, enter their key phrase, list of target terms, and have the option of selecting an article censor year. The article censor year limits the text search to articles published from the beginning of the text index (18th century) through the end of the specified year, allowing users to see what results may have looked like in years prior. For convenience, we provide quick fill target term lists for genes, transcription factors, ligands, microRNA, and drugs and devices. After submission, queries enter the processing queue. Upon completion, typically within minutes, logged in users receive an email notification.\n\nWhen viewing the results table for a particular query (see Figure 3), users are presented with a dynamic list and a p-value threshold slider. The threshold slider controls the Fisher’s exact test p-value by which target terms are filtered, and defaults to a value of 1 × 10−5. Moving the slider or entering a value in the threshold box automatically updates the content of the displayed term list. A graph shows a curve representing the sorted list of all target term p-values and the current selected cutoff, giving users a visual representation of their filter. With this, users can investigate their top hits further as they see fit. Finally, users also have the option of downloading the entire list of target term counts, or the current filtered list based on their selected threshold.\n\n\nResults\n\nGiven that the corpus used for our web application is different from the original KinderMiner publication, we need to validate that our new index produces results of similar quality. To do this, we query the same cell reprogramming tasks from the KinderMiner algorithm publication, using the same key phrases, target lists, and censor years. Specifically, we run queries to discover and rank important transcription factors for creating induced pluripotent stem cells (iPS cells), cardiomyocytes, and hepatocytes. For each of the queries, we use the same list of 2,243 transcription factors from the original publication (available as a quick-fill option in the application) and search against the key phrases “embryonic stem cell”, “cardiomyocyte”, and “hepatocyte” respectively. To validate findings for each, we compare the top hits with relevant factors found by the earliest landmark papers for each discovery. Furthermore, we censor each query to only include articles from the earliest publications in our text index (18th century) through December 31 of the year two years prior to the landmark publications (e.g. for the iPS discovery, which was first published in 2006, we include articles through December 31, 2004). Thus, positive findings demonstrate early discovery of the landmark findings and KinderMiner’s potential for prioritizing and expediting the discovery process. For the iPS cell discovery, we censor to articles published through December 31, 2004, and the relevant transcription factors we consider are KLF4, LIN28, MYC, NANOG, POU5F1, and SOX26–8, though we do also note that POU5F1 and SOX2 constitute a sufficient subset for iPS reprogramming9. For cardiomyocytes, we censor to articles published through December 31, 2008, and consider GATA4, HAND2, MEF2C, NKX2-5, and TBX510,11. For hepatocytes, we censor to articles published through December 31, 2009, and consider CEBPB, FOXA3, FOXA2, GATA4, HNF1A, HNF4A, and MYC12,13. We use a term filter p-value threshold of 1 × 10−5 for all of them. In every case, our KinderMiner web application recovers the same positive hits in the top 20 as in the original publication.\n\nHowever, this initial evaluation does not necessarily confirm that KinderMiner performs any better than other state-of-the-art tools. We thus compare our cell reprogramming results from KinderMiner with those from other similar text mining tools. While there have been many algorithms proposed around the concept of co-occurrence counting, we found only three tools comparable to KinderMiner available: FACTA+14, Polysearch215, and BEST16. There are other similar sounding tools like DeepLife17 and Life-iNet18, but DeepLife serves more as a general biomedical web search than a term ranking tool and Life-iNet does not appear to have any code or application available for use. All three of FACTA+, Polysearch2, and BEST allow the user to rank a list of biomedical entities (analogous to the KinderMiner target terms) by their association with a query entity (analogous to the KinderMiner key phrase), and all allow general text entry for the query entity. Unlike KinderMiner, however, they all perform some form of biomedical entity labeling and indexing for their entity lists. While this approach has advantages, it also limits user queries to the predefined vocabularies of entities that are provided by each tool. KinderMiner is more flexible as it allows users to rank and filter a list of any text terms they like against any text key phrase that they like.\n\nPerhaps the closest comparison tool to KinderMiner is BEST, as it provides a “Transcription Factor” option for one of its predefined entity lists. It also provides the option to censor its corpus search by year, giving us the greatest ability to compare with KinderMiner’s censored results. FACTA+ and Polysearch2 do not have predefined transcription factor lists, but do have “Gene/Protein” and “Genes/Proteins” options respectively. We use these lists as the closest approximation. FACTA+ and Polysearch2 also do not have an option to censor the corpus by year, so they have the advantage of many more years of text as compared to KinderMiner and BEST. For all tools, we use the same three key phrases (“embryonic stem cell”, “cardiomyocyte”, and “hepatocyte”) as query entities. We performed all searches for comparison on February 3, 2020.\n\nTable 1, Table 2, and Table 3 show the top 20 transcription factors determined by each method on these three cell reprogramming tasks. Important transcription factors that appear in the top 20 hits for each method and cell type are highlighted in blue, with duplicate hits highlighted in orange (FACTA+ only). Recall@20 is shown in the bottom row of each table.\n\nLandmark factors are highlighted in blue (duplicates in orange) and the bottom row shows Recall@20. All methods find a sufficient set of factors (POU5F1 and SOX2). Note that KinderMiner and BEST have been censored to articles published through 2004, whereas the other methods have no such censoring, giving them the advantage of access to the landmark papers and more.\n\nshows Recall@20. Note that KinderMiner and BEST have been censored to articles published through 2008, whereas the other methods have no such censoring, giving them the advantage of access to the landmark papers and more.\n\nLandmark factors are highlighted in blue and the bottom row shows Recall@20. Note that KinderMiner and BEST have been censored to articles published through 2009, whereas the other methods have no such censoring, giving them the advantage of access to the landmark papers and more.\n\n\nUse cases\n\nOf course, KinderMiner is designed to be general enough to work for other biomedical applications. In fact, it has already been used as part of several other published applications. In one, KinderMiner was used to validate phenotypes found to be associated with FMR1 premutation as part of electronic health record (EHR) analysis19. In that case, KinderMiner helped provide evidence that FMR1 premutation carriers experience a clinical profile different from that of a control population. In another application, KinderMiner was used to assess novelty of lab tests as predictors for certain diseases20. In that work, EHR analysis revealed that common lab tests are sometimes predictive of diagnoses for which they would not typically be used. KinderMiner was used to validate the novelty of those findings by using the opposite-handed statistical test and an inverse ranking function. KinderMiner has also been used to identify protein-protein interactions21, outperforming Polysearch2 in that work as well. Finally, the original KinderMiner publication also demonstrated its use to identify potential drug repositioning candidates for diabetes3, finding several relevant hits and providing comparable results to a more sophisticated computational approach.\n\n\nDiscussion\n\nFrom Table 1, we note that all methods perform comparably on the iPS cell reprogramming task, and all do in fact find a sufficient set of reprogramming factors9 (POU5F1 and SOX2) in the top hits. Recall again, however, that FACTA+ and Polysearch2 have access to literature available years after the landmark discoveries were made, whereas KinderMiner and BEST have both been censored to articles published through 2004 (two years prior to discovery). KinderMiner also finds all five relevant factors for cardiomyocytes in the top 11 hits of Table 2, and finds most factors for hepatocyte reprogramming in the top nine hits of Table 3, outperforming the comparison methods by recall for both cardiomyocyte and hepatocyte reprogramming. Furthermore, KinderMiner is not limited to predefined vocabularies like all of the comparison methods. The string matching and counting approach used by KinderMiner is both simpler and more flexible while performing comparably if not better than the predefined vocabulary approach. In general, approaches like KinderMiner’s tend to achieve high recall without requiring annotated training data22.\n\nEven just these three results show how valuable KinderMiner can be in a research work flow. The resulting list provided by KinderMiner not only provides researchers with suggested reading, but also allows them to prioritize their targets for experimentation. Consider the discovery of how to make iPS cells before it was known. If one assumes a priori that 2–3 transcription factors are needed, then the task quickly becomes unmanageable without some prioritization of the roughly 2,000 human transcription factors ((2,0002)=2.0×106 and (2,0003)=1.3×109). If a researcher wants to know if NANOG is associated with pluripotency, they can use a search engine to find and read specific articles about that single connection. That, however, is only one finding, and the researcher has to know what connection they are looking for (NANOG and pluripotency) beforehand. If a researcher instead wants to know which of all roughly 2,000 transcription factors are most likely associated with pluripotency according to the current state of the literature, the required reading would be infeasible. Furthermore, after extensive reading, the researcher still needs to synthesize that knowledge into an ordered set of the most promising leads to try as reprogramming factors to make iPS cells. This is exactly the type of situation where KinderMiner shines. In a matter of seconds to minutes, that same researcher can get an ordered list of promising leads to help them prioritize their reading or experimentation.\n\n\nLimitations and future work\n\nWhile KinderMiner performs well empirically, it is not without limitations. One potential shortcoming is the lack of negation handling. Because KinderMiner only looks for document level co-occurrence, it cannot distinguish between a positive or negative association. For example, if many articles contain phrases like “Gene A is not associated with tissue B,” KinderMiner will still likely pick up on this relation between gene A and tissue B and produce it as a significant hit. We are currently exploring options for addressing negation. Nevertheless, even with this lack of negation handling, KinderMiner performs well on a variety of tasks.\n\nAnother potential shortcoming of KinderMiner is that, in some cases, the exact matching approach requires more curation from the user. Exact text matches are immediately useful when the list of target terms is something like genes, where well-defined lists are available and where it may be important to distinguish between similar names like TWIST1 and TWIST2, but it becomes more challenging when the target term list is more complicated. For example, a target term list of ICD9 codes would be more challenging. ICD diagnosis descriptions are often very specific or contain tokens that would not typically appear in the literature, thus requiring curation if they are to be used for a target term list. For example, “Malignant neoplasm of breast (female); unspecified site” is unlikely to occur as an exact string or set of tokens in the literature, so this term would require manual modification (e.g. to “malignant breast cancer”) before use with KinderMiner. This minor difficulty is effectively a tradeoff made in exchange for the flexibility of being able to use any list of target terms as text.\n\nOne possible way to alleviate some of limitations of exact string matching is to build in a synonym matcher. KinderMiner does not have this feature at this time. Thus, a match to POU5F1, for example, will not also include matches to OCT4. Similarly, KinderMiner does not currently perform any stemming, which means that tokens like “pluripotent” and “pluripotency” are not counted identically. KinderMiner still performs well without either synonym matching or stemming, and while they may increase true hits, they may also increase false hits. Nevertheless, synonym matching and stemming are areas of future work that we are actively working on and evaluating.\n\nFurther areas of interest include using named entity recognition to help disambiguate tokens like the gene “WAS” from the verb, features to filter the corpus content by more than just publication year, and Bayesian methods to modulate term ranks. Of course, this is not an exhaustive list of possible improvements. There are numerous research directions we may investigate and incorporate into the tool as they prove useful.\n\nRegarding KinderMiner’s speed, the primary factor that determines the time to complete a request is the length of the target term list. Based on our own tests with target term lists ranging from thousands to tens of thousands in length, requests currently take roughly 12 milliseconds per target term. Thus, a request on a list of roughly 2,000 transcription factors works out to around 24 seconds, or around 4 minutes for a request on all roughly 20,000 human genes. Of course, heavy traffic on the web application could also affect response time as requests are queued on a first-come first-serve basis. We do not anticipate an issue in the short term, but we are actively investigating queueing and batch querying options to improve speed and user experience even further.\n\nFinally, while we consider the KinderMiner web application to be a living tool that will improve and change over time, we want to be able to provide users with reproducible results. To address this, we eventually intend to allow users to select from a backlog of text indices going back one or two years.\n\n\nConclusions\n\nWe present the first publicly available implementation of the KinderMiner algorithm. It includes a user-friendly interface and is built on top of a fast and local index of PubMed abstracts. We demonstrate the utility of the KinderMiner web application on the task of identifying transcription factors likely to be useful to reprogram cells to a particular state, but the tool is general and can be used to help prioritize any biomedical experiment or address any biomedical question of interest to the user.\n\nOur example results suggest that, even though KinderMiner is simple and derives its results from correlations already present in the literature, it can synthesize those correlations into a coherent single discovery not yet commonly known. We plan to continue to improve the KinderMiner web application with quarterly updates, by addressing limitations, improving the interface, and by responding to suggestions from the community.\n\n\nData availability\n\nThe PubMed abstract corpus we use is available for download as the National Library of Medicine’s “Annual Baseline” Dataset4.\n\n\nSoftware availability\n\nThe KinderMiner web application is freely available for use by everyone at https://www.kinderminer.org.\n\nCode to download, process, and index PubMed abstracts is available at https://github.com/iross/km_indexer.\n\nArchived code as at time of publication: https://doi.org/10.5281/zenodo.394849823.\n\nLicense: MIT\n\nCode for the web application itself is available at https://github.com/stewart-lab/kinderminer_webapp.\n\nArchived code as at time of publication: https://doi.org/10.5281/zenodo.394700824.\n\nLicense: MIT",
"appendix": "References\n\nPautasso M: Publication growth in biological sub-fields: patterns, predictability and sustainability. Sustainability. 2012; 4(12): 3234–3247. Publisher Full Text\n\nBornmann L, Mutz R: Growth rates of modern science: a bibliometric analysis based on the number of publications and cited references. J Assoc Inf Sci Technol. 2015; 66(11): 2215–2222. Publisher Full Text\n\nKuusisto F, Steill J, Kuang Z, et al.: A simple text mining approach for ranking pairwise associations in biomedical applications. AMIA Jt Summits Transl Sci Proc. 2017; 166–174. PubMed Abstract | Free Full Text\n\nUS National Library of Medicine: Medline/pubmed citation records. 2019. Reference Source\n\nEurope PMC Consortium: Europe pmc: a full- life sciences and platform for innovation. Nucleic Acids Res. 2014; 43: D1042–D1048. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTakahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4): 663–676. PubMed Abstract | Publisher Full Text\n\nYu J, Vodyanik MA, Smuga-Otto K, et al.: Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858): 1917–1920. PubMed Abstract | Publisher Full Text\n\nTakahashi K, Tanabe K, Ohnuki M, et al.: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5): 861–872. PubMed Abstract | Publisher Full Text\n\nHuangfu D, Osafune K, Maehr R, et al.: Induction of pluripotent stem cells from primary human fibroblasts with only oct4 and sox2. Nat Biotechnol. 2008; 26(11): 1269–1275. PubMed Abstract | Publisher Full Text\n\nIeda M, Fu JD, Delgado-Olguin P, et al.: Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; 142(3): 375–386. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAddis RC, Ifkovits JL, Pinto F, et al.: Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success. J Mol Cell Cardiol. 2013; 60: 97–106. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang P, He Z, Ji S, et al.: Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature. 2011; 475(7356): 386–389. PubMed Abstract | Publisher Full Text\n\nKogiso T, Nagahara H, Otsuka M, et al.: Transdifferentiation of human fibroblasts into hepatocyte-like cells by defined transcriptional factors. Hepatol Int. 2013; 7(3): 937–944. PubMed Abstract | Publisher Full Text\n\nTsuruoka Y, Miwa M, Hamamoto K, et al.: Discovering and visualizing indirect associations between biomedical concepts. Bioinformatics. 2011; 27(13): i111–i119. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu Y, Liang Y, Wishart D: PPolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more. Nucleic Acids Res. 2015; 43(W1): W535–W542. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee S, Kim D, Lee K, et al.: Best: next-generation biomedical entity search tool for knowledge discovery from biomedical literature. PLoS One. 2016; 11(10): e0164680. PubMed Abstract | Publisher Full Text | Free Full Text\n\nErnst P, Siu A, Milchevski D, et al.: Deeplife: An entity-aware search, analytics and exploration platform for health and life sciences. In: The 54th Annual Meeting of the Association for Computational Linguistics.2016; 19–24. Reference Source\n\nRen X, Shen J, Qu M, et al.: Life-inet: A structured network-based knowledge exploration and analytics system for life sciences. In: Proceedings of ACL 2017, System Demonstrations.2017; 55–60. Reference Source\n\nMovaghar A, Page D, Brilliant M, et al.: Data-driven phenotype discovery of FMR1 premutation carriers in a population-based sample. Sci Adv. 2019; 5(8): eaaw7195PubMed Abstract | Publisher Full Text | Free Full Text\n\nKleiman R, Kuusisto F, Ross I, et al.: Machine learning assisted discovery of novel predictive lab tests using electronic health record data. AMIA Jt Summits Transl Sci Proc. 2019; 2019: 572–581. PubMed Abstract | Free Full Text\n\nRaja K, Natarajan J, Kuusisto F, et al.: Automated extraction and visualization of protein–protein interaction networks and beyond: A text-mining protocol. Methods Mol Biol. Springer, New York, NY. 2020; 2074: 13–34. PubMed Abstract | Publisher Full Text\n\nJunge A, Juhl Jensen L: Cocoscore: Context-aware co-occurrence scoring for text mining applications using distant supervision. Bioinformatics. 2020; 36(1): 264–271. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoss I: iross/km_indexer: Creating a new release, now that zenodo is activated. (version v1.1). 2020. http://www.doi.org/10.5281/zenodo.3948498\n\nKuusisto F: stewart-lab/kinderminer_webapp: First release for publication. (version v1.0). 2020. http://www.doi.org/10.5281/zenodo.3947008"
}
|
[
{
"id": "82000",
"date": "19 Apr 2021",
"name": "Qingyu Chen",
"expertise": [
"Reviewer Expertise I assess mainly based on the computational side. The impacts on the biomedical knowledge side also need to be assessed."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes a tool for efficient discovery on potential associations of terms in biomedical literature. Given a list of terms of interest and a query phrase, it matches and ranks the documents at the abstract level. It also provides a case study to demonstrate its usage. The tools are also publicly available. I have a few comments on the evaluation, limitation, and functionality summarized below.\nMy primary comment is the precision and recall of the term matching part should be quantified. Given only a simple string matching method is used, it will potentially miss identifying the same entities using different expressions or wrongly identify the entities using exact terms but represent differently (for example, some genes share the same names with chemicals). Importantly, this is the first step of the algorithm; errors would propagate to the later stages. It is therefore critical to provide a detailed evaluation on this part. In addition, does the indexing part incorporate synonyms? The descriptions are not very clear.\n\nOther comments are relatively minor. A primary comment is the limitation should also specify the application is limited to the abstract level only. Also, in terms of the function, please considering providing an API so that potential users can query the associations systematically.\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? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "7568",
"date": "20 Dec 2021",
"name": "Finn Kuusisto",
"role": "Author Response",
"response": "We greatly appreciate Dr. Chen's patience, time, and effort in providing useful feedback and corrections. > A primary comment is the limitation should also specify the application is limited to the abstract level only. We did not emphasize the fact that our search is only at the abstract level in the limitations section. This was simply an oversight, and we have now added it to the limitations section. > Please consider providing an API so that potential users can query the associations systematically. This is certainly a feature we have considered, and we intend to update the software with new backend data and features according to user demand. If it becomes a common request, we will absolutely implement it. > In addition, does the indexing part incorporate synonyms? We do not perform any synonym matching as implemented but have explored it as an option and do ultimately intend to incorporate some version of it in the future. One major issue that we have found with synonym matching though is that, while it has the potential to increase recall, it can also substantially decrease precision. For example, one synonym of the gene name POU5F1 is OCT3, but OCT3 is also a synonym of SLC22A3, and this is not a particularly unique case even in the simple domain of gene names. Similar situations also frequently occur with acronyms, such as DR for Diabetic Retinopathy. To elaborate further, in our exploration of synonym matching we ran the “embryonic stem cell” example with and without synonyms. While POU5F1, NANOG, and SOX2 show up in the top 7 hits without synonyms, the search with synonyms didn’t even include SOX2 in the top 20 and NANOG was pushed to hit 16. This is due at least in part to several hits getting inflated counts due to synonym collisions with other words and each other. SPI1, TAF1, PAX6, and NR4A2 show up as hits number 3, 4, 5, and 7 respectively when we ran the search with synonyms. This is likely because both SPI1 and TAF1 have the synonym “OF,” PAX6 has a synonym “AN,” and NR4A2 has a synonym “NOT.” It appears then that synonym matching alone could very possibly lead to a substantial tradeoff in precision. We have clarified that KinderMiner does not perform synonym matching and increased emphasis of this point in the limitations section. Given that this a software paper rather than a full research paper, we chose to share this tool with the simpler approach of exact string matching without synonyms because of its flexibility and because it has been demonstrated to work well for us under most circumstances. > My primary comment is the precision and recall of the term matching part should be quantified. Given only a simple string matching method is used, it will potentially miss identifying the same entities using different expressions or wrongly identify the entities using exact terms but represent differently (for example, some genes share the same names with chemicals). Importantly, this is the first step of the algorithm; errors would propagate to the later stages. Dr. Chen and Dr. Orimaye have both commented on the limitations of using exact string matching. While we agree that exact string matching has potential limitations, we argue that exact string matching has advantages as well. Primarily, exact string matching allows for rapid exploration of the literature versus ontologies or semantic matching methods. Building ontologies or semantic models for any category of biomedical entity requires a great deal of time and effort, whereas exact matching allows for the quick creation of custom lists of entities of interest, which we found to be a common desire among our colleagues at the bench. Instead of looking for a tool that provides a predefined entity set that seems closest to their interests, they can simply create a list on the fly and run a search. Furthermore, as new terms arise (e.g., genes or drugs), the ontologies or semantic models need to be reworked/retrained rather than simply adding a string to the end of a list. The trade-off is that some entities may require manual curation and a possible sacrifice in recall in some cases. Further, semantic matching approaches, or even simple synonym matching as we described with the embryonic transcription factor above, have the potential to introduce errors of their own when the simple exact match works as is. That said, we understand and appreciate the concern for our approach, have attempted to clarify this in the limitations section, and have elaborated on how we are considering more advanced matching for future versions. > It is therefore critical to provide a detailed evaluation on this part. Dr. Chen has requested a detailed evaluation of our choice to use exact string matching versus others. Given that this paper is on a software implementation of a previously published algorithm, and because the flexibility afforded by allowing any list of entities makes an exhaustive evaluation of recall and precision an expansive research undertaking, we feel this request is out of scope for this paper. Even an evaluation of recall for our exact string matching on a single gene, such as HNF1A, would require a gold standard labeling of HNF1A-related abstracts for our entire index. In order to more generally evaluate how our exact matching performs on the entire human gene domain would then require nearly 20000 more distinct gold standard abstract labelings of our index. This in turn would be true of every other domain that our algorithm might encounter, including entity lists like proteins, drugs, diseases, cell types, species names, and so on. Because the output of the algorithm is an ordered subset of entities of interest, we have opted instead to present compelling results on several gold standard lists for important discoveries, rather than focusing on how the algorithm may miss individual entities of interest. Exact string matching provides great flexibility by allowing a user to search any list of entities, but this comes at the risk that some important entities may not surface due to say a particularly unpopular spelling. We think the flexibility is worth the tradeoff and that the promising results we have seen justify the decision. We greatly appreciate the Dr. Chen's patience, time, and feedback. We intend for this software tool to give more researchers access to a simple algorithm that has helped us to prioritize some of our own research over the years. Overall, despite limitations, we find that the empirical results speak for themselves and hope that others will find it useful too."
}
]
},
{
"id": "83813",
"date": "12 May 2021",
"name": "Sylvester O. Orimaye",
"expertise": [
"Reviewer Expertise Natural Language Processing",
"Machine Learning",
"Literature-Based Discovery",
"Computational Linguistics",
"Bioinformatics",
"Biostatistics",
"Public Health."
],
"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 presented KinderMiner web interface for ranking biomedical experiments. The KinderMiner algorithm was previously published and can be used for other Biomedical knowledge search tasks such as identifying transcription factors for reprogramming cells.\nWhile there are a series of limitations around the current version of the algorithm and the web interface, as stated by the authors, the web interface could benefit users in terms of user-friendliness and efficiency (search response time). In particular, the lack of latent semantic processing capability could significantly limit the results of the algorithm. It cannot be over-emphasized that semantically related concepts found in many ontologies have increasingly become an essential part of search engines. The authors should seriously consider this concept in their future versions.\nThe authors could also explain the rationale behind setting the Fisher's exact threshold to 0.00005. How was the point determined? What would be the difference (in terms of recall or p@20) between the results if a different threshold was to be used? Would it be statistically significant?\nI found minor typos such as \" we need to validate...\" even though the authors described the experiment in the past. Please check for other typos in the final version of the manuscript.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "7569",
"date": "20 Dec 2021",
"name": "Finn Kuusisto",
"role": "Author Response",
"response": "We greatly appreciate the Dr. Orimaye's patience, time, and effort in providing useful feedback and corrections. > The authors could also explain the rationale behind setting the Fisher's exact threshold to 0.00005. We used 0.00001 for the Fisher’s Exact Test threshold. In this case we simply used the same search parameters as those that we used in the original KinderMiner algorithm publication. That said, we did not have a rigorous statistical justification for the threshold in the original paper. Instead, we chose the 1e-5 threshold, as it frequently resulted in final ranked lists in the range of 50 to 100 hits, which was a reasonable size when presenting results to collaborators working at the bench. We stuck with that choice for our own internal use of the algorithm and for comparison to the original here, but we provide the interactive slider in the webapp for flexibility and exploration of resultant list sizes. We have elaborated on this choice in the paper. > It cannot be over-emphasized that semantically related concepts found in many ontologies have increasingly become an essential part of search engines. Dr. Chen and Dr. Orimaye have both commented on the limitations of using exact string matching. While we agree that exact string matching has potential limitations, we argue that exact string matching has advantages as well. Primarily, exact string matching allows for rapid exploration of the literature versus ontologies or semantic matching methods. Building ontologies or semantic models for any category of biomedical entity requires a great deal of time and effort, whereas exact matching allows for the quick creation of custom lists of entities of interest, which we found to be a common desire among our colleagues at the bench. Instead of looking for a tool that provides a predefined entity set that seems closest to their interests, they can simply create a list on the fly and run a search. Furthermore, as new terms arise (e.g., genes or drugs), the ontologies or semantic models need to be reworked/retrained rather than simply adding a string to the end of a list. The trade-off is that some entities may require manual curation and a possible sacrifice in recall in some cases. Further, semantic matching approaches, or even simple synonym matching as we described with the embryonic transcription factor above, have the potential to introduce errors of their own when the simple exact match works as is. That said, we understand and appreciate the concern for our approach, have attempted to clarify this in the limitations section, and have elaborated on how we are considering more advanced matching for future versions. > I found minor typos such as \" we need to validate...\" even though the authors described the experiment in the past. Please check for other typos in the final version of the manuscript. We have corrected that typo and have checked the manuscript for other typos. We greatly appreciate Dr. Orimaye's patience, time, and feedback. We intend for this software tool to give more researchers access to a simple algorithm that has helped us to prioritize some of our own research over the years. Overall, despite limitations, we find that the empirical results speak for themselves and hope that others will find it useful too."
}
]
}
] | 1
|
https://f1000research.com/articles/9-832
|
https://f1000research.com/articles/10-626/v1
|
21 Jul 21
|
{
"type": "Research Article",
"title": "Modeling individual development plans, mentoring support, and career preparedness relationships among Doctor of Philosophy (Ph.D.) trainees in the life sciences",
"authors": [
"Chi-Ning Chang",
"Clinton A. Patterson",
"Nathan L. Vanderford",
"Teresa M. Evans",
"Chi-Ning Chang",
"Nathan L. Vanderford",
"Teresa M. Evans"
],
"abstract": "Background: As greater career development support for doctoral students and postdoctoral researchers has been emphasized, the individual development plan (IDP) has become a recommended mentoring tool. However, little is known about the effect of IDPs on mentoring and career development. This study proposed two conceptual models to examine the interrelationships among the use of IDPs, mentoring support, and career preparedness with a diverse sample of doctoral students and postdoctoral researchers in the life sciences. Methods: The data leveraged for this study was collected over a three-month period, March 2016 to June 2016, as part of a cross-sectional, online survey. The survey was distributed through social media and direct email to participants enrolled in life/biological/medical or physical/applied doctoral programs at U.S. institutions. To test the proposed conceptual models, this study employed the design-based multilevel structural equation modeling. Results: The analytic sample comprised 660 doctoral students and postdoctoral researchers in the life sciences from 91 institutions. The results suggested that 1) using the IDP could enhance mentoring support and career preparedness of doctoral students and postdoctoral researchers; 2) greater mentoring support and career preparedness would motivate mentees to continue utilizing the IDP with their principal investigator (PI) or advisor; and 3) females, postdoctoral researchers, and international scholars might need more support throughout the mentoring and career development process. Conclusions: This research demonstrated the empirical evidence an IDP has within mentorship and career preparedness, and that an IDP is an important career development tool that enhances trainees’ overall career preparation.",
"keywords": [
"Individual Development Plan",
"Mentoring support",
"Career development",
"Doctoral education",
"Postdoctoral training"
],
"content": "Introduction\n\nAt the core, doctoral education is intended as a career development catalyst. For example, doctoral students not only build their disciplinary foundation but also demonstrate capability of conceptualizing and conducting research through their dissertation research. Experts agree that successful doctoral programs mentor dependent students1–4 and develop them into independent scholars.2,5–7 However, today is a challenging time for many doctoral students and postdoctoral researchers, regardless of discipline. Pressures such as time to degree,8,9 student attrition,10,11 mental health-related issues,12,13 and the most recent challenges of the coronavirus disease 2019 (COVID-19) pandemic further emphasize the need for improved career development associated with the doctoral and postdoctoral environment.\n\nOver the past decade a method used to elicit, support, and facilitate doctoral education dialogue emphasizing mentorship and career development is the individual development plan (IDP). This mentorship communication and career development tool is designed to elicit trainee development through self-reflection. Although IDP usage in non-academic sectors began in the last century when managers and organizations would align an individual’s competencies within an IDP,14 the higher educational framework of the IDP was not introduced until 2002, when the Federation of American Societies for Experimental Biology15 developed the IDP for postdoctoral fellows in the life sciences. The most established example of the IDP is the web-based version titled “myIDP”, which is a step-by-step platform that guides users through a process of (1) self-assessment, (2) career exploration, (3) goal-setting, and (4) implementation.16\n\nSubsequent literature has suggested how individuals in graduate education and postdoctoral training can benefit from IDP adoption to identify and develop career readiness, by developing skills (i.e., technical, professional or transferable), that enhance exploration and/or awareness of career paths.17–19 Researchers discovered that IDPs appear to be most effective when doctoral students and postdoctoral researchers not only have a positive mentoring relationship with their advisor, but are able to engage in career development activities.20,21 Recent IDP research indicates that 51% of surveyed doctoral students reported that the IDP was helpful to their career development.21 The IDP is intended to be a vehicle doctoral students and postdocs can use to identify their career goals.22 However, IDP research highlights the need to close long-standing career development infrastructure gaps within institutions and external funding solicitations that impede an individual’s career development.8,21–24 For example, integrating career development experiences early and often within the doctoral curriculum, institutions can encourage an expanded career readiness within their trainees by “hiring PhD scientists to direct career development programs”.23 Knowing that mentorship is closely associated with IDP effectiveness, faculty development programs designed to improve mentoring, and especially the mentor’s familiarity with the IDP process, are critical.8,18–24 However, Hobin and other researchers determined that only 20% of mentors were familiar with the IDP process.20 Additional IDP research discovered that mentees report having completed the IDP but not having discussions with their mentor21 and mentors often may not help postdocs with career development because the postdoc did not ask for their input.20\n\nFalling under the larger recommendation to increase scholarship of mentoring,25 there are calls19,21,22,24 for more studies to determine the effectiveness and uniqueness of IDPs, which is where this study is situated. This study further examines the impacts of the IDP by investigating the interrelationships among the IDP, mentoring support, and career preparedness for postdoctoral researchers and doctoral students. Our hypotheses are formed from existing IDP literature,20,21,24 whereby two models are envisioned: 1) the IDP enhances an individual’s mentoring support and career preparedness, and 2) mentoring support and career preparedness predict the use of IDPs, as shown in Figure 1. Meanwhile, the mentee’s backgrounds are also functioning over the process.\n\n\nMethods\n\nThis research is part of a health and wellbeing study approved by the University of Kentucky (protocol 15-1080-P2H) and University of Texas Health San Antonio (protocol HSC20160025X) institutional review boards. Respondents read a cover page and consent was obtaining through the online survey web link. Survey responses were anonymous, and participants were ensured of confidentiality.\n\nThe data leveraged for this study was collected as part of a cross-sectional, online survey in the spring and early summer of 2016. Survey invitations were distributed via direct email to randomly chosen United States (U.S.) institutions with graduate-level programs. The survey was also shared on social media (primarily Twitter and LinkedIn) and shared with individuals by email from random institutions that have graduate-level programs. To participate in the research, respondents had to be doctoral students and postdoctoral researchers at a United States (U.S.) institution. Exclusion criteria for the current study were the humanities and social science respondents from the original data set.\n\nMentoring support and career preparedness were collected using the five-point Likert scale from strongly disagree to strongly agree. Mentoring Support (MS) was constructed by four items, such as: “MS-1. My Principal Investigator (PI)/advisor provides real mentorship”, “MS-2. My PI/advisor is an asset to my academic and professional career”, “MS-3. My PI/advisor provides ample support”, and “MS-4. My PI/advisor positively impacts my emotional or mental wellbeing.” Career Preparedness (CP) was measured by four items including: “CP-1. I am on track to complete my training”, “CP-2. I am well prepared for completing my training”, “CP-3. I am confident about my career prospects”, and “CP-4. I am prepared for my post-training career.” The Cronbach’s alphas for MS and CP are.864 and.905, respectively. In addition to these two primary measures, we also asked participants to report the use of the IDP (i.e., whether or not they completed an IDP annually with their PI/advisor). Other individual demographic information was collected and treated as covariates, such as gender, doctoral student/postdoctoral trainee, race/ethnicity, and citizenship status. The survey questionnaire and data set are freely accessible online.26,27\n\nTo test the proposed conceptual models shown in Figure 1, this study employed the design-based multilevel structural equation models28,29 by using Mplus 8.6.30 This approach allows us to test the interrelationships among the variables simultaneously, handle the measurement error issue, and correct the underestimated standard errors due to the nested data structure (students clustered with institutions). Other open-source software like the lavaan.survey package in R could be also used to conduct the same analysis.31\n\nThe models not only highlight the primary variables (IDP, mentoring support, and career preparedness), but also consider that the individual background characteristics are functioning over the process. In the analysis, for each primary variable, we also controlled for gender (female = 1; male = 0), doctoral student/postdoctoral trainee (postdoctoral trainee = 1; doctoral student = 0), race/ethnicity (Black/Hispanic/Native Americans = 1; the rest of racial groups = 0), and citizenship status (international scholar =1; citizen or permanent resident = 0). The final Mplus code and the data set we used for the analysis can be accessed at an online data repository.32\n\n\nResults\n\nA total of 864 Ph.D. trainees from 116 institutions participated in the survey. After excluding those respondents who were not in Life/Biological/Medical Sciences, the final analytic sample consisted of 660 doctoral students and postdoctoral researchers from 91 institutions. Among our sample (N = 660), 22% were postdoctoral researchers, 74% were female, 10% were underrepresented minorities (i.e., Black/Hispanic/Native Americans), 10% were international students/researchers, and 39 % reported they completed an IDP annually with their PI/advisor. The descriptive results for all measures and demographic information are shown in Table 1.\n\n\n\n▪ MS-1. My PI/advisor provides real mentorship\n\n\n\n▪ MS-2. My PI/advisor is an asset to my academic and professional career\n\n\n\n▪ MS-3. My PI/advisor provides ample support\n\n\n\n▪ MS-4. My PI/advisor positively impacts my emotional or mental wellbeing\n\n\n\n▪ CP-1. I am on track to complete my training\n\n\n\n▪ CP-2. I am well prepared for completing my training\n\n\n\n▪ CP-3. I am confident about my career prospects\n\n\n\n▪ CP-4. I am prepared for my post-training career\n\n\n\n▪ Female\n\n\n\n▪ Postdoctoral Fellow\n\n\n\n▪ Black/Hispanic/Native Americans\n\n\n\n▪ International Scholars\n\nThe statistical results indicate that model 1 adequately fits the empirical data: Root Mean Square Error of Approximation (RMSEA) = .034; Comparative Fit Index (CFI) = .965; Standardized Root Mean Squared Residual (SRMR) = .031. As shown in Figure 2, the standardize factor loadings in the model are all greater than.70, indicating good measurement validity for constructing the latent factors (mentoring support and career preparedness).\n\nNote. Value is standardized path coefficient. The values on the light arrows are standardized factor loadings. Given that the use of the IDP is binary, the coefficients on the path from variables to IDP are standardized probit coefficients. The Primary variables (IDP, mentoring support, and career preparedness) are controlled by gender, doctoral student/postdoctoral fellow, race/ethnicity, and citizenship status. Only the statistically significant paths are shown in the figure. The reference group of the IDP is the trainee who did not use the IDP with their PI/advisor annually. The reference group of females is male. The reference group of Postdoctoral fellows is doctoral student. The reference group of international scholars is citizen or permanent resident. Oval represents a latent factor (measured by a set of indicators). Rectangle stands for an observed variable. MS-1 to MS-4 are the observed indicators of mentoring support, while CP-1 to CP-4 are the observed indicators of career preparedness. The full description for each of these indicators is shown in Table 1. *p < .05 **p < .01 ***p < .001.\n\nControlling for the individual background characteristics, the results in Figure 2 reveal that the IDP shows positive effects on mentoring support (β = .27, p < .001) and career preparedness (β = .17, p < .01); at the same time, mentoring support is also a mediator between the IDP and career preparedness. These results suggest the use of an IDP could enhance a mentee’s career preparedness through mentoring support. With regard to individual background, we find that postdoctoral researchers (β = −.37, p < .001) and international scholars (β = −.59, p < .001) were less likely to use the IDP annually with their PI/advisor. Females had lower career preparedness (β = −.13, p < .05) than males, but there are no significant differences among racial groups in the use of IDP, mentoring support, and career preparedness.\n\nOverall, the use of the IDP, mentoring support, and background characteristics can account for 26% of the variance in career preparedness. The use of the IDP and background characteristics can explain 8% of the variance in mentoring support. The background characteristics can account for 5% of the variance in the use of the IDP. The unexplained variances imply that there are other unknown contributing factors also relating to these three primary variables.\n\nThe statistical results indicate that model 2 also adequately fits the empirical data (RMSEA = .034; CFI = .965; SRMR = .031). In Figure 3, the standardize factor loadings in the model also show good measurement validity for constructing the latent factors (mentoring support and career preparedness).\n\nNote. Value is standardized path coefficient. The values on the light arrows are standardized factor loadings. Given that the use of the IDP is binary, the coefficients on the path from variables to IDP are standardized probit coefficients. The Primary variables (IDP, mentoring support, and career preparedness) are controlled by gender, doctoral student/postdoctoral fellow, race/ethnicity, and citizenship status. Only the statistically significant paths are shown in the figure. The reference group of the IDP is the trainee who did not use the IDP with their PI/advisor annually. The reference group of females is male. The reference group of Postdoctoral fellows is doctoral student. The reference group of international scholars is citizen or permanent resident. Oval represents a latent factor (measured by a set of indicators). Rectangle stands for an observed variable. MS-1 to MS-4 are the observed indicators of mentoring support, while CP-1 to CP-4 are the observed indicators of career preparedness. The full description for each of these indicators is shown in Table 1. *p < .05 **p < .01 ***p < .001.\n\nOver and above the background characteristics, the results in Figure 3 indicate that mentoring support has a positive effect on career preparedness (β = .46, p < .001), while both mentoring support (β = .17, p < .01) and career preparedness (β = .19, p < .01) positively predict the use of the IDP. Multiple significant paths from background characteristics to three primary variables provide additional warnings. We found that the lower mentoring support (β = −.23, p < .05) for postdoctoral researchers might partially explain why they were less likely to use the IDP (β = −.28, p < .05). For international scholars, their lower career preparedness (β = −.31, p < .01) indirectly revealed why they used the IDP less than U.S. citizens or permanent residents (β = −.54, p < .01).\n\nOverall, mentoring support, career preparedness, and individual background characteristics can explain 15% of the variance in the use of the IDP. The mentoring support and individual background characteristics can account for 24% of the variance in career preparedness. The individual background characteristics can explain only 1% of the variance in mentoring support. The unexplained variances mean that there are other unknown factors, which were not included and collected by this study.\n\n\nDiscussion\n\nAs greater career development support for doctoral students and postdoctoral researchers has been emphasized, the IDP has become a commonly used mentoring tool in science, technology, engineering, and mathematics (STEM) fields. Although this tool is encouraged, its effect on mentoring support and career development is still understudied. To fill the gaps, this study investigated 660 doctoral students and postdoctoral researchers in the life sciences to test the two conceptual models by using the design-based multilevel structural equation models. The empirical evidence supports the two proposed conceptual models and connects the relationships among the use of the IDP, mentoring support, and career preparedness.\n\nIn the first model, we found that using the IDP can enhance mentoring support and career preparedness; meanwhile, greater mentoring support, the higher level of career preparedness. Our findings affirm the IDP in practice, joining other IDP research20,21,24,33 that encourage mentees to utilize the IDP to self-assess current skills and create a strategic plan with their mentor. Mentor and mentee continually prioritize and revisit the IDP to track progress and refine objectives, whereby mentees eventually achieve their career goals with mentoring support. In the second model, our finding aligned with previous research20,21,24 and extend the evidence that greater mentoring support and career preparedness are associated with the use of the IDP. Although the reasons remain unknown and possibly complex, our result is similar to Hobin’s research finding that career development discussions between mentors and postdocs are often absent or lacking,20 or ‘underutilized’.33 Given that IDP can establish a long-term mentorship, it is not surprising that mentees will continually hold IDP discussions with their PI or mentor when they perceive a need for mentoring support and get closer to their career goals. Recent IDP research provides evidence for enabling a customized or flexible IDP implementation process that promotes a learner-centered approach and aligns with recent higher education aspirations.33\n\nThis study also examined how individual background characteristics were functioning over the process. Although our results provide evidence for how the IDP and mentorship can encourage career preparedness, female trainees showed a lower career preparedness than males. Females have historically experienced notable and significant STEM challenges, such as negative stereotypes, hostile environments, and trainee identity.34–36 Recently, mentorship was discovered to predict high levels of gender-STEM identity for women.35 Aligned with an ever-increasing (and needed) higher education movement at National Institute of Health (e.g. BEST, Common Fund, T32) and National Sciences Foundation (e.g., NRT, Louis Stokes, AGEP), we recommend that institutions and faculty members should pay more attention to female scholars. Specifically, we suggest continued reduction of the STEM barriers and negative stereotypes for women, and expanded mentorship to underrepresented students in career preparedness skill development that enables a student’s transition into wider range of STEM-related careers.17,25,33,37 Additionally, the results reveal that international scholars and postdoctoral researchers were less likely to use the IDP. The lower career preparedness for international scholars and the lower mentoring support for postdoctoral researchers might explain why these trainee populations used the IDP less than their counterparts. We encourage their PIs or mentors to use some well-established IDP platforms (e.g., myIDP) to identify their career goals and create action plans every year. We also recommend that mentors provide a safe and welcoming atmosphere where career preparedness discussions are the norm, not the expectation, even if that means more faculty mentoring development is needed.20,21,25\n\nWhile our findings show important implications for the IDP research, there are still several limitations to this study. First, the data collection (summer 2016) may be considered dated. However, our research goal was to examine the effect of the IDP. We believe it is still acceptable to use the empirical evidence to test our conceptual models. Second, even though we identified the interrelationships among the use of the IDP, mentoring support, career preparedness, and individual background characteristics, there might be other unknown factors omitted from this study, such as the different types of IDP tools, the quality of IDP discussion, etc., which could be investigated in the future studies. Third, the present study was cross-sectional and not able to properly infer the longitudinal effect of the use of the IDP. Finally, although our sample is not nationally representative, our survey sample included a diverse group of doctoral students and postdoctoral researchers in the life/biological/medical fields from 91 institutions.\n\nDespite these limitations, this study makes methodological and practical contributions to the literature on IDP and extends the scholarship of mentoring.25 First, it is one of first empirical studies to propose conceptual models for IDP research and examines the interrelationships among the IDP, mentoring support, and career preparedness with a diverse sample of doctoral students and postdoctoral researchers. Second, instead of using descriptive results to indicate the disparities of individual backgrounds in each of primary variables, this study showed how the background characteristics are functioning over the process. Third, and importantly, the findings provide the graduate and postdoctoral education community with empirical evidence and implications for the use of the IDP, as well as the important need to improve mentor training.8,19–21,24 In short, our study suggests that using the IDP could provide career development support for both doctoral trainees and postdoctoral researchers in the life sciences.\n\nImplementation of IDPs to improve doctoral education, postdoctoral training, and faculty mentoring will produce diversity and flexibility through meaningful and transformative educational experiences for each trainee. Especially in the current COVID-19 context, these factors will be of vast importance for the future of our research and training enterprise. This research demonstrated the empirical evidence an IDP has within mentorship and career preparedness, and offered further implications the IDP is an important career development tool that enhances trainees overall career preparation.\n\n\nData availability\n\nFigshare: Modeling individual development plans, mentoring support, and career preparedness relationships among Ph.D. trainees in the life sciences. https://doi.org/10.6084/m9.figshare.14893116.v1.26\n\nFigshare: Survey Questions - Modeling individual development plans, mentoring support, and career preparedness relationships among Ph.D. trainees in the life sciences. https://doi.org/10.6084/m9.figshare.14893182.v1.27\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.5055803.32\n\nLicense: Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Competing interests\n\n\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe author(s) declared that no grants were involved in supporting this work.\n\n\nReferences\n\nDenecke D, Feaster K, Stone K: Professional development: Shaping effective programs for STEM graduate students. Wash DC Counc Grad Sch. 2017.\n\nMa Y, Mukherjee S, Uzzi B: Mentorship and protégé success in STEM fields. Proc Natl Acad Sci. 2020; 117(25): 14077–83. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWelton AD, Mansfield KC, Lee P-L, et al.: Mentoring educational leadership doctoral students: Using methodological diversification to examine gender and identity intersections. Int J Educ Leadersh Prep. 2015; 10(2): 53–81.\n\nWoolderink M, Putnik K, van der Boom H, et al.: The Voice of PhD Candidates and PhD Supervisors. A Qualitative Exploratory Study amongst PhD Candidates and Supervisors to Evaluate the Relational Aspects of PhD Supervision in the Netherlands. 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NSF 18-304 [Internet]. 2018 [cited 2021 Apr 1]. Reference Source\n\nCouncil of Graduate Schools: PhD completion and attrition: Analysis of baseline demographic data from the PhD completion project. [Internet].2008. Reference Source\n\nMaher MA, Wofford AM, Roksa J, et al.: Exploring Early Exits: Doctoral Attrition in the Biomedical Sciences. J Coll Stud Retent Res Theory Pract. 2020 Aug; 22(2): 205–26. Publisher Full Text\n\nEvans TM, Bira L, Gastelum JB, et al.: Evidence for a mental health crisis in graduate education. Nat Biotechnol. 2018; 36(3): 282–4. PubMed Abstract | Publisher Full Text\n\nLevecque K, Anseel F, De Beuckelaer A, et al.: Work organization and mental health problems in PhD students. Res Policy. 2017 May; 46(4): 868–79. Publisher Full Text\n\nPickett L: Competencies and managerial effectiveness: Putting competencies to work. Public Pers Manag. 1998; 27(1): 103–15. Publisher Full Text\n\nFASEB: Individual Development Plan for Postdoctoral Fellows [Internet].2002. Reference Source\n\nHobin J, Fuhrmann C, Lindstaedt B, et al.: You Need a Game Plan [Internet]. Science AAAS. 2012 [cited 2021 Apr 1]. Reference Source\n\nFuhrmann CN, Halme DG, O’sullivan PS, et al.: Improving graduate education to support a branching career pipeline: Recommendations based on a survey of doctoral students in the basic biomedical sciences. CBE Life Sci Educ. 2011; 10(3): 239–49. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMathur A, Chow CS, Feig AL, et al.: Exposure to multiple career pathways by biomedical doctoral students at a public research university. PloS One. 2018; 13(6): e0199720. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVincent BJ, Scholes C, Staller MV, et al.: Yearly planning meetings: individualized development plans Aren’t just more paperwork. Mol Cell Forum. 2015; 58(5): 718–21. PubMed Abstract | Publisher Full Text\n\nHobin JA, Clifford PS, Dunn BM, et al.: Putting PhDs to work: career planning for today’s scientist. CBE Life Sci Educ. 2014; 13(1): 49–53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVanderford NL, Evans TM, Weiss LT, et al.: A cross-sectional study of the use and effectiveness of the Individual Development Plan among doctoral students. F1000Res. 2018 Jul 5 [cited 2021 Apr 1]; 7(722). PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nTsai JW, Vanderford NL, Muindi F: Optimizing the utility of the individual development plan for trainees in the biosciences. Nat Biotechnol. 2018; 36(6): 552–3. PubMed Abstract | Publisher Full Text\n\nFuhrmann CN: Enhancing graduate and postdoctoral education to create a sustainable biomedical workforce. Hum Gene Ther. 2016; 27(11): 871–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVanderford NL, Evans TM, Weiss LT, et al.: Use and effectiveness of the Individual Development Plan among postdoctoral researchers: findings from a cross-sectional study. F1000Res. 2018 Oct 25 [cited 2021 Apr 1]; 7(1132). PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nCommittee on Effective Mentoring in STEMM, Board on Higher Education and Workforce, Policy and Global Affairs, National Academies of Sciences, Engineering, and Medicine: The Science of Effective Mentorship in STEMM [Internet]. In: Byars-Winston A, Dahlberg ML, editors. Washington, D.C.: National Academies Press; 2019 [cited 2021 Apr 1]. Reference Source\n\nChang C-N, Patterson C, Vanderford N: Modeling individual development plans, mentoring support, and career preparedness relationships among Ph.D. trainees in the life sciences [Internet].2021 [cited 2021 Jul 1]. Publisher Full Text\n\nChang C-N, Patterson C, Vanderford N, et al.: Survey Questions: Modeling individual development plans, mentoring support, and career preparedness relationships among Ph.D. trainees in the life sciences.2021 [cited 2021 Jul 1]; Publisher Full Text\n\nGagne JR, Chang C-N, Fang H, et al.: A multimethod study of inhibitory control and behavioural problems in preschoolers. Infant Child Dev. 2019; 28(1): e2115. Publisher Full Text\n\nWu J-Y, Kwok O: Using SEM to analyze complex survey data: A comparison between design-based single-level and model-based multilevel approaches. Struct Equ Model Multidiscip J. 2012; 19(1): 16–35. Publisher Full Text\n\nMuthén LK, Muthén B: Mplus user’s guide: Statistical analysis with latent variables, user’s guide.Muthén & Muthén; 1998-2017.\n\nOberski D: lavaan.survey: An R Package for Complex Survey Analysis of Structural Equation Models. J Stat Softw [Internet]. 2014 [cited 2021 Jul 1]; 57(1). Reference Source\n\nChang C-N, Patterson C, Vanderford NL, et al.: MPLUS Code - Modeling individual development plans, mentoring support, and career preparedness relationships among Ph.D. trainees in the life sciences [Internet]. Zenodo; 2021 [cited 2021 Jul 1]. Publisher Full Text\n\nEason DE, Bruno BC, Böttjer-Wilson D: Individual Development Plans (IDPs): An Underutilized Advising Tool in the Geosciences. Geol Soc Am. 2020; 30(7): 34–5. Publisher Full Text\n\nAppel M, Kronberger N, Aronson J: Stereotype threat impairs ability building: Effects on test preparation among women in science and technology. Eur J Soc Psychol. 2011; 41(7): 904–13. Publisher Full Text\n\nClarke P, Hirsch JA, Melendez R, et al.: Snow and Rain Modify Neighbourhood Walkability for Older Adults. Can J Aging. 2017; 36(2): 159–69. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHill C, Corbett C, St Rose A: Why so few? Women in science, technology, engineering, and mathematics . Washington DC: American Association of University Women; 2010.\n\nNational Academy of Sciences, National Academy of Engineering, and Institute of Medicine: Expanding Underrepresented Minority Participation: America’s Science and Technology Talent at the Crossroads [Internet]. Washington, D.C.: National Academies Press; 2011 [cited 2021 Apr 1]. Reference Source"
}
|
[
{
"id": "90084",
"date": "02 Aug 2021",
"name": "Adriana Bankston",
"expertise": [
"Reviewer Expertise Higher education policy"
],
"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 a robust characterization of the relationship between the IDP, mentoring support, and career preparedness for trainees, which is necessary for supporting graduate students and postdocs in universities. I agree with the characterization that, while this study is from 2016, the data are relevant for comparing these models and the study is valuable for the community to be aware of, and the conclusions are appropriate. The sample size and number of institutions examined also make this a robust study with important results for higher education.\nThe observation that the IDP is most effective when mentoring is positive and when trainees can engage in career development activities is an interesting one, which also extends to questions related to how mentoring relationships could be improved and what systemic changes need to occur in order for career development activities to be more accepted and included into the training of graduate students and postdoctoral researchers as important components to prepare them for skill building and future jobs. For example, a recent study from PLOS Biology (Brandt et al., 2021) showed that involvement in career development activities for PhD students is not detrimental to their research productivity.\nTo this end, it was disappointing but informative to see that only 20% of mentors were familiar with the IDP process, and that in many cases mentees completed them but did not discuss them with mentors. To an extent, I agree that the mentee needs to take charge of their professional development and make sure to complete the IDP and take the initiative to set up meetings with their mentor to discuss results. But this also points to the fact that we need to incentivize a higher number of mentors to learn about the IDP, think about how institutions can assist with this goal, and whether there are positive model institutions where this occurs regularly to be used as a model for others. I’m not sure what is currently being mandated by institutions across the country in terms of the IDP. A good discussion point in terms of future directions would be to talk about incentives for mentors to use the IDP for supporting their mentees in their career development and whether institutions can put in place a reward system for those that show consistently positive results in order to improve the enterprise as a whole.\nIndeed, the report suggests that only 39% reported that they completed an IDP annually with their mentor, which isn’t a very high number considering the number of graduate students and postdocs we are training in our universities. Moreover, it seems that postdocs and international trainees aren’t using the IDP as much, which is also unfortunate to see. One question for discussion would be to think about what kind of support for career development graduate students need, which may be different from those of postdocs, and how the IDP may potentially be adapted to better suit these needs in the future. In addition, we know that international researchers typically receive less career support, and I would be curious to explore this more as to whether they use the IDP less due to language barriers or other factors that may make them feel uncomfortable to discuss career options with their mentors. Given the importance of international trainees for advancing research forward and the high percentage of the research workforce that is foreign-born with U.S. laboratories, it would be important to address how we can support them more in the discussion section.\nIn terms of the survey results, I was wondering if there were any negative answers given on mentoring (or if that was an answer option) and whether trainees felt that lack of mentoring led to them feeling less prepared for a particular career path. This type of analysis could be a useful impetus for discussing systemic changes that need to occur to better support mentees, both from the perspective of the mentors and the institutions. This question could be a follow-up study to look at systemic issues and solutions to address them.\nI appreciated the remarks made in relation to IDP and long-term mentorship, as I think it’s useful to think about how often mentees approach their mentors about career goals and making sure that these conversations occur at regular intervals throughout their training. It would be useful to do a study on how often meetings between mentors and mentees related to professional and career development typically occur in universities. Given that career goals can change, I would argue this needs to occur more frequently than once a year. A longitudinal study of career development discussions that occur at various timepoints during the training of a graduate student or postdoc could be very informative.\nOne question I had is whether the study results represent only STEM graduate students and postdocs, or whether they are specific to life sciences (which is more a subset of STEM). I would suggest clarifying this information in the methods section. I would also like to know more about the list of disciplines that were analyzed in the survey (if beyond STEM), and whether humanities and social sciences trainees responded differently to the survey questions as compared to those in STEM. The latter could provide useful insights into the effectiveness of the IDP.\nI would have also liked to see a breakdown between data at particular institutions, in terms of whether these mentoring relationships and consequent IDP discussions are better or worse at R1 institutions versus those that are less research intensive, such as MSIs and HBCUs for example.\nIt may be interesting to survey the same population again now, in 2021 to assess pandemic impacts on the factors examined in this publication. The pandemic is likely to alter the dynamics between mentors and mentees. I would be curious to know if a higher number of trainees are completing the IDP since they are working from home using their computers. Also, if they are less able to perform bench science under the current circumstances, has this led to trainees focusing more on their career development during the pandemic and what lessons can we learn from this?\nI would like to see more of discussion on diversity aspects of this study and how different ethnic groups used and/or benefitted from the IDP (for example BIPOC, LGBTQ etc. if these options were included), as well as how these variables intersect. For example, was there a difference between the career support that female graduate students received versus female postdocs, knowing these needs may be different? What about women of color at both career stages? It would be important to discuss more details about how this kind of career advice occurs and develop some recommendations for institutions to implement programs that may address these issues for particular populations.\nFinally, I thought the models proposed were interesting and thought provoking, as well as important for explaining this complicated dynamic. But I would consider a third model, where institutions also play a role, because institutional policies may dictate how some of these interactions take place. For example, the model could be Institutional support -> mentor support -> IDP -> career preparedness, or Institutional support -> mentor support/IDP as parallel tracks -> career preparedness. In this case, mentoring and IDP could both help with career development, where mentoring either encourages the IDP or could be parallel to it, but both are dictated by institutional policies. In a systemic sense, I think it’s worthwhile considering how institutions can better incentivize mentoring and career development. Future surveys could include questions on how institutions should help graduate students and postdocs with career preparedness in addition to individual mentors, as well as how we can better prepare mentors to provide the necessary advice and guidance to their trainees.\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": "7571",
"date": "17 Dec 2021",
"name": "Clint Patterson",
"role": "Author Response",
"response": "Thank you for the review. We do agree with all the comments and wish to communicate your critique has been helpful as we revised the article. We are noting: Much of your feedback points to an excellent framework for future mentorship research, which we believe is important for future directions of mentoring. For example, you identified good discussion points about incentives for mentors to use the IDP and how institutions reward or value IDPs in mentoring relationships. Additionally, negative answers given to mentoring, either as a response option or open-ended response, were not included in the collected data. However, we agree with your recommendation that this mentoring relationship theme poses an important follow-up or future line of inquiry. We do agree a follow-up study that investigates institutional systemic mentoring issues and solutions to address these issues is important to high quality mentoring relationships. Your discussion point about how the COVID-19 pandemic is impacting IDP usage, research productivity, and career development is important. We believe such research could offer valuable perspectives for mentorship and the ever-evolving future workforce needs. The IDP is approached as a living document, and customizable in many ways, including what the mentee identifies as salient topic(s) at that moment, and which topic(s) they wish to share with their mentor(s). As such, identifying the career development needs of graduate students can be emergent and unique to the individual. We do note career development coursework is a growing and effective trend in graduate education (source). In our data sample section, we stated we removed the participant responses from a non-life sciences perspective. Therefore, our sample is fully associated with life sciences. We agree that broadening this research to include STEM and non-STEM (i.e., humanities, social sciences) would offer valuable insights into IDP implementation and effectiveness. We reviewed the collected data and determined most institutions were not MSI and/or HBCU. Unfortunately, we do not have a large and diverse enough sample to appropriately answer if IDP usage differs at institutions (i.e., R1s, MSIs, HBCUs) but agree this would be an intriguing line of future research and findings could offer specific institutional implications for mentorship. Additionally, our study’s variable was the biological gender. We recommend future studies that investigate how the IDP is incorporated and/or benefits marginalized populations (BIPOC, LBGTQ, etc.). Lastly, your suggestion to make the institutional role more explicit with the models make sense; however, we do not have the data to support this recommendation. However, the idea aligns with two emerging notions in literature and is of interest for our authorship team. First, The Science of Effective Mentoring in STEMM (2019) reports institutions certainly influence the mentoring environment at their school, and even offered examples (including an IDP) for formalizing mentorship within and across the institution. Institutional approaches to mentoring are not only lines of inquiry, but also an implementation area, for some of our authorship team members. For example, the recent Transformative Doctoral Education Model (TDEM) explicitly recognizes the institution (including programs, mentors, and doctoral student) as an internal driver for the doctoral ecosystem. Again, our thanks to the reviewer for their thoughtful feedback and insightful recommendations for this study and future IDP research considerations."
}
]
},
{
"id": "90082",
"date": "11 Aug 2021",
"name": "Jessica K Polka",
"expertise": [
"Reviewer Expertise Open science",
"scholarly communication",
"early career researchers"
],
"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\nNote that I don't have adequate expertise to evaluate the structural equation modeling in this paper, hence my provisional approval.\nIn \"Modeling individual development plans, mentoring support, and career preparedness relationships among Doctor of Philosophy (Ph.D.) trainees in the life sciences,\" Chang et al. analyze data from a survey of doctoral students. The design of the survey appears sound, and the resulting data enable the authors to draw valuable conclusions about IDP usage, its relationship to demographic variables, and its correlation with mentoring support and career preparedness.\nMy most substantial questions surround the use of structural equation modeling, which I lack the expertise to adequately assess. I believe this work should be reviewed by an expert in that area. Nevertheless, a few issues arose for me:\n\nThe statistical results are identical for both models. Does this mean that one model cannot be favored over the other, and thus, that the causal relationships can be described as a positive feedback loop, with IDP usage supporting career preparedness & mentoring support, and vice versa? Is it then possible to represent such a circular relationship in a new model, and would such a model fit the data better?\n\nWhy are arrows between career preparedness & mentoring support not bidirectional in both cases? For example, imagine the trainee has good career preparedness from other sources (peers, society, internet resources, institution, etc) and has therefore selected a mentor on the basis of their support, or is therefore proactively seeking mentorship.\nI also have a few more minor points:\nIn the \"Conclusions\" section of the abstract, I'm not understanding the first part of the sentence, which states that evidence is demonstrated but does not seem to specify the conclusion.\n\nIn Methods (Data/sample) - \"Survey invitations were distributed via direct email to randomly chosen United States (U.S.) institutions with graduate-level programs,\" where were these email addresses found? Do these represent emails of graduate program coordinators, or students themselves, as implied in the following sentence?\n\nIn Results, the sentence beginning \"With regard to individual background\" could perhaps be more logically presented in a separate section about the survey responses independent of the two models.\n\nThroughout the text, proofreading could help to improve readability.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7572",
"date": "17 Dec 2021",
"name": "Clint Patterson",
"role": "Author Response",
"response": "Thank you for the feedback and review of our study. We appreciate your perspective, questions, and recommendations. We appreciate the reviewer’s question about the model fit issue. For the first question, in SEM, changing the direction of one or more paths in a model will yield an equivalent model. Equivalent models will result in precisely the same model fit. That is why our two models showed the identical model fit results (RMSEA = .034; CFI = .965; SRMR = .031). Therefore, we are not able to evaluate if one model was favored over the other, which was also not the purpose of this study. Our goal was to test if 1) the IDP enhances an individual’s mentoring support and career preparedness, and 2) mentoring support and career preparedness predict the use of IDPs. Each of the results showed the positive relationships among these three focal variables with a good model fit. For the second question, we could test a new model with a circular relationship, but the model fit will be the same given that we just change the direction of paths in the model. Therefore, we think our original models already show a good model fit to answer our research questions. We appreciate reviewer’s question and comments about the relationship between mentoring support and career preparedness. In this study, we considered mentoring support is one of the inputs for career preparedness (output), which was aligned with the mentoring literature (i.e., process-oriented model of mentoring; Eby et al., 2013). That was why we tested the path from mentoring support to career preparedness in both models theoretically. In practice, we agree that it is possible that trainees with good career preparedness proactively seek mentorship. To address the reviewer’s concern, we conducted additional tests for models 1 and 2 by correlating mentoring support and career preparedness (bidirectional). In updated model 1, IDP showed significantly positive effects on mentoring support (β = .27, p < .001 vs. β = .27, p < .001) and career preparedness (β = .28, p < .001), while mentoring support and career preparedness were positively correlated with each other (β = .43, p < .001). In updated model 2, both mentoring support (β = .15, p < .01) and career preparedness (β = .28, p < .01) positively predicted the use of the IDP, while mentoring support and career preparedness were positively correlated with each other (β = .38, p < .001). The updated results were still very similar and consistent with our original findings, so we decided to keep our original models and results as is in the paper. Thank you for the minor point about the “Conclusions” section of the abstract, which is now revised -- “This research offered empirical evidence for how an IDP, mentorship, and career preparedness interact. Findings revealed the IDP enhances mentoring support and career preparedness, as well as mentoring support and career preparedness predict IDP use. We conclude the IDP is an important mentorship tool that enhances trainees’ overall career preparation.” We appreciate your point about the Methods (Data/sample). The data was collected using a sample of convenience. We included institutions that made emails publicly available on their websites. These emails could have included trainees and/or program leadership including program directors or coordinators. The study was promoted on Twitter and LinkedIn, and posts were shared widely by social media users. Thank you for the feedback in the Results section. We ran an additional analysis to test the differences of each variable by background characteristics. This revised manuscript now includes an expanded “Sample characteristics and descriptive results” section and new Table 2 is included in this revised manuscript. Thank you again for your article review and methodological questions. We sincerely appreciated the feedback and incorporated into what we believe is a stronger revision."
}
]
}
] | 1
|
https://f1000research.com/articles/10-626
|
https://f1000research.com/articles/10-1294/v1
|
17 Dec 21
|
{
"type": "Research Article",
"title": "Liability from the use of medical artificial intelligence: a comparative study of English and Taiwanese tort laws",
"authors": [
"Dennis W. K. Khong",
"Wan-Ju Yeh",
"Wan-Ju Yeh"
],
"abstract": "Background: Modern artificial intelligence applications are appearing in healthcare and medical practices. Artificial intelligence is used both in medical research and on patients via medical devices. The aim of this paper is to examine and compare English and Taiwanese tort laws in relation to medical artificial intelligence. Methods: The methodologies employed are legal doctrinal analysis and comparative law analysis. Results: The investigation finds that English tort law treats wrong diagnostic or wrong advice as negligent misstatement, and mishaps due to devices as a physical tort under the negligence rule. Negligent misstatement may occur in diagnosis or advisory systems, while a negligent act may occur in products used in the treatment of the patient. Product liability under English common law applies the same rule as negligence. In Taiwan, the general principles of tort law in Taiwan’s Civil Code for misstatement and negligent action apply, whereas the Consumer Protection Act provides for additional rules on product liability of traders. Conclusions: Safety regulations may be a suitable alternative to tort liability as a means to ensure the safety of medical artificial intelligence systems.",
"keywords": [
"Tort liability",
"Medical artificial intelligence",
"English law",
"Taiwanese law",
"Product liability"
],
"content": "Introduction\n\nModern artificial intelligence applications are appearing in healthcare and medical practices (Nordlinger et al., 2020). As a result, the question of exposure to risk and liability from the use of artificial intelligence in medical practices is a question that haunts the medical fraternity.\n\nIn this paper, English and Taiwanese tort laws will be examined to identify the similarities and differences in their approaches, in order to determine the liability from medical artificial intelligence systems. In addition, they serve as a means of comparison between a common law jurisdiction and a civil law jurisdiction.\n\nThe field of artificial intelligence began with the appearance of the first computers in the 1950s. Alan Turing (1950) proposed an ‘imitation game’, now known as the Turing test, to determine whether a machine can be said to be ‘intelligent’. The term ‘artificial intelligence’ was coined by John McCarthy in 1956 when he organised the Dartmouth Summer Research Project on Artificial Intelligence to gather the various experts in the emerging computational fields at that time (Moor, 2006).\n\nMore recently, advancements using machine learning, deep learning and artificial neural network techniques have made artificial intelligence applications practical and feasible. The massive availability of clinical and imagery data coupled with exponential improvement in processing power have fuelled the growth and development of artificial intelligence in the area of healthcare and medical practice.\n\nMedical artificial intelligence technology is used both in biomedical research as well as on patients. Muralli and Sivakumaran’s (2018) survey found artificial intelligence applications in healthcare to include managing medical records and data, doing repetitive jobs, treatment design, digital consultation, drug creation, detecting malignant diseases, detecting mental conditions, recognition of facial symptoms, management of diabetes and robot-assisted surgery. Avanzo et al. (2021) identified clinical applications of artificial intelligence such as imaging, therapy and quality assurance. The benefits of adopting artificial intelligence in healthcare have been identified by Meskó and Görög (2020), which include improving in-person and online consultation, health assistance and medication management, AI-driven diagnostics, mining medical records, precision medicine, designing treatment plans, drug creation and triage tools.\n\nThe risks of using medical artificial intelligence may be accompanied by defects in product manufacturing, design, or insufficiency in the description of product or instruction of use. Patients are indirect users of medical artificial intelligence since they do not decide on the selection, quality, operation, and maintenance of medical artificial intelligence devices, but are the beneficiaries of such devices through the actions of medical professionals.\n\nThe discussion on tort liability of medical artificial intelligence goes back to the early days of rule-based medical expert systems (Adams & Gray, 1987; Cannataci, 1989). More recently, this discussion has continued in both legal and medical literature. The legal discussions focus primarily on American law (Allain, 2013; Pesapane et al., 2018; Price et al., 2019; Sullivan & Schweikart, 2019; 吳采薇, 2020), although investigations from the European (Minssen et al., 2020; Pesapane et al., 2018) and Taiwanese perspectives (吳佳琳, 2020; 陳鋕雄, 2019) have also been made.\n\nOne common thread of discussion is on who is liable for injury caused by the failure of an artificial intelligence system (Allain, 2013; Junod, 2019). Another common approach is to consider tort liability as a form of product liability of the manufacturer or software developer (Allain, 2013; Frank, 2019; Jabri, 2020; Molnár-Gábor, 2020). It is thought that one way for addressing the risk is through regulation (Kamalnath, 2018; Minssen et al., 2020; Pesapane et al., 2020; Price, 2017), although a no-fault insurance solution has also been proposed as a way to compensate victims (Smith & Fotheringham, 2020).\n\nArtificial intelligence systems can at times be enigmatic. Techniques such as deep learning perform their designated task without it being clear as to how it is done. Such tools are treated as black boxes which become problematic when they are being evaluated by regulators and used to determine liability (Macrae, 2019; Price, 2017, 2018).\n\nInterestingly, Khan (2016) raises the question of a practitioner’s liability for failure to follow the advice of an artificial intelligence system which later turns out to be the correct advice. To investigate this question, Tobia, Nielsen and Stremitzer (2021) conducted an online experiment with respondents as potential jurors and found that practitioners are less likely to be held liable by the respondents if they followed the advice, provided that the advice is not unusual.\n\nA doomsday scenario was raised by Froomkin, Kerr and Pineau (2019) who warned of a future where artificial intelligence systems outperform doctors which may lead to the danger of over-reliance on medical artificial intelligence. Finally, a cautionary word was raised by Maliha et al. (2021), who warn not to over-emphasise the risk and liability of artificial intelligence to the extent of hindering the development and progress of useful and novel applications of medical artificial intelligence.\n\n\nMethods\n\nEmploying a legal doctrinal methodology, which involves identifying the meaning and principles in statutory law and court decisions using a literal and sometimes, a teleological interpretation method to the legal text (Westerman, 2011; Hutchinson & Duncan, 2012), this paper examines tort law liability arising from artificial intelligence applications in medical practice from the perspectives of English and Taiwanese laws. English law is the origin of the common law family of legal systems, whereas Taiwanese law is an example of civil law system in an Asian country. The case laws studied herein are selected from a standard tort law textbook (Goudkamp & Nolan, 2020; Khong, 2021). Goudkamp & Nolan (2020) was chosen as the reference for English law as it has been the leading textbook on English tort law since the first edition in 1937. The legal doctrinal methodology is used to identify how a common law approach differs from a civil law approach to the same question. The first author analysed English law while the second author did the same for Taiwanese law in this research. This research does not employ any statistical data and no human respondents were involved.\n\nResearch ethics approval for this research has been granted by the Research Ethics Committee of the Multimedia University, Approval Number EA0692021. No human respondents, and therefore no consent therefrom, are involved in this research.\n\n\nResults\n\nEnglish tort law is not statutory in nature and is continuously being developed through case law. Generally, torts are categorised into informational torts and physical torts. In the context of artificial intelligence, liability arising from an informational tort may be due to an insufficient or outdated knowledge base, defective algorithms or coding, or even the inappropriate use of artificial intelligence tools by the users; while liability from a physical tort may be due to faulty equipment or sensors, or that the algorithm is not fit for its task.\n\nInformational tort\n\nIn contemporary English tort law, liabilities from wrongful information are classified as negligent misstatement and deceit.\n\nThe principal case for negligent misstatement is Hedley Byrne & Co Ltd v Heller & Partners Ltd, where it was held that “if someone possessed of a special skill undertakes, quite irrespective of contract, to apply that skill for the assistance of another person who relies upon such skill, a duty of care will arise. The fact that the service is to be given by means of or by the instrumentality of words can make no difference.” This is refined in Smith v Bush, where the court, relying on the UK Unfair Contract Terms Act 1977, rejected the use of disclaimers as they are not fair to consumers. The tort of negligent misstatement applies to medical artificial intelligence because information and advice given by artificial intelligence systems are bespoke and customised to each patient based on their needs.\n\nUnlike negligent misstatement, deceit requires proof of ‘fraud’ or ‘recklessness as to the truth’ on the part of the defendant: Derry v Peek. It is very unlikely that the tort of deceit applies to medical artificial intelligence, for there will be a lack of an intention to commit fraud.\n\nPhysical tort\n\nPhysical torts in English law are classified into intentional torts and unintentional torts. Intentional torts usually come in the form of trespass, and in the case of medical artificial intelligence, battery, while unintentional torts under the negligence rule.\n\nIn Cole v Turner, Holt CJ declared that “the least touching of another in anger is a battery.” Later, in Collins v Wilcock, Goff LJ provided a more contemporary and general definition of battery: “the physical contact so persisted in has in the circumstances gone beyond generally acceptable standards of conduct.” Two types of exceptions to battery are recognised: lawful control and exigencies of everyday life, and consent.\n\nThe most common type of unintentional tort in English law is negligence. Lord Atkin in the House of Lords’ opinion in Donoghue v Stevenson stated that “negligence [is] based upon a general public sentiment of moral wrongdoing for which the offender must pay.” To succeed in negligence, apart from showing that the defendant owed a duty of care to the plaintiff, three other elements have to be satisfied: that the defendant breached his duty, the damage is foreseeable, and the plaintiff suffered damage. For breach of duty, Baron Alderson in Blyth v Birmingham Waterworks Co held that “[n]egligence is the omission to do something which a reasonable man, guided upon those considerations which ordinarily regulate the conduct of human affairs, would do, or doing something which a prudent and reasonable man would not do.” Thus, the standard of care for negligence is the reasonable man standard.\n\nLikewise, the standard of care of a professional is that of a reasonable professional. In the case of medical practitioners, Bolam v Friern Hospital Management Committee established that a doctor “is not guilty of negligence if he has acted in accordance with a practice accepted as proper by a responsible body of medical men skilled in that particular art.” For some time, it was thought that the Bolam principle absolves the doctor if he proves that what he did accords with the practice of “a responsible body of medical men.” However, in Bolitho v City and Hackney Health Authority, the House of Lords opened the opportunity for judges’ intervention “if, in a rare case, it can be demonstrated that the professional opinion is not capable of withstanding logical analysis, the judge is entitled to hold that the body of opinion is not reasonable or responsible.”\n\nAdditionally, Donoghue v Stevenson serves to illustrate two other principles. First, it is an example of product liability law, where a consumer can sue a manufacturer outside contract law. Secondly, it supports the concept of corporate liability as Stevenson is the name of the manufacturer appearing on the label. The approach of the English courts is to assume that the defendant as a business entity is responsible or vicariously liable for the negligence of its employees.\n\nOn the distinction between intentional tort and negligence, the test is whether the injury was inflicted intentionally, not whether the action of the alleged tortfeasor was intentional: Letang v Cooper.\n\nTaiwan, being a Civil Law jurisdiction, has statues as the basis for tort liability. Article 184 of the Civil Code covers the general scenario: “A person who, intentionally or negligently, has wrongfully damaged the rights of another is bound to compensate him for any injury arising therefrom.”\n\nUnder the Civil Code, insufficiency of or error in thr information provided by a party which cause injuries or damage is considered as an infringement of a person’s freedom to make correct decisions. Physical injury to a person, whether intentionally or negligently, is treated as an infringement to the integrity of his health of body. Damages for infringements of rights can be claimed according to Article 184 of the Civil Code. Damages for pain and suffering can be an additional heading of compensation.\n\nAdditional protection is afforded through Article 7 of the Consumer Protection Act: “Traders engaging in designing, producing or manufacturing of goods or in the provisions of services, shall ensure that goods or services provided meet and comply with the contemporary technical and professional standards with reasonably expected safety requirements. … Traders shall be jointly and severally liable in [sic] violating the foregoing paragraphs and thereby causing injury or damage to consumers or third parties, provided that if traders can prove that they have not been negligent, the court may reduce damages.”\n\nAccording to the Taiwan High Court Civil Judgment, 109 San-Yi No. 139, liability arising from the use of medical devices may be in two forms: product liability for medical devices, and tort liability for medical services. To attribute responsibility for injuries caused by medical devices, the court must judge, on a case-by-case basis, whether it is a product liability, tort liability or both. Damages due to a combination of product liability and tort liability will be shared by the manufacturer of the medical device and the medical service provider.\n\n\nDiscussion\n\nImposing liability on tortfeasors for causing harm serves the purposes of compensating the victim and incentivising potential tortfeasors to take care. Despite this, both English common law and the Taiwanese tort law appear to concentrate primarily on the compensatory aspects. Therefore, safety regulations by the medical authorities are additionally needed to ensure the safety of such devices.\n\nBoth informational torts and physical torts are covered by English and Taiwanese tort laws. Harm from medical artificial intelligence is likely to be unintentional and thus come under the negligence rule.\n\nOne difference between the laws in both jurisdictions is on the treatment of product liability. In English law, if a manufacturer can mount a defence indicating that what he has done is reasonable, or in medical treatment cases is the same as what other practitioners would have done, then he is absolved of all blame and liability. However, in Taiwanese law, this kind of defence will only partially reduce the amount of his damages.\n\nErroneous information or advice provided by medical artificial intelligence devices is treated as an informational tort, whereas mishaps due to machines or robotic devices are categorised as physical tort. Both are likely to be unintentional torts in English and Taiwanese tort laws.\n\n\nConclusion\n\nThe aim of this paper is to examine English and Taiwanese tort laws in relation to medical artificial intelligence, and to highlight the similarities and differences in their approaches.\n\nIt is found that English tort law treats wrong diagnostic information or advice as negligent misstatement and mishaps due to devices as a form of physical tort under the negligence rule. The negligence rule is applied similarly to product liability under English common law.\n\nOn the other hand, the general principles of tort law in Taiwan’s Civil Code apply to misstatement and negligent actions. Additionally, its Consumer Protection Act imposes product liability on traders for liability from defective medical artificial intelligence systems.\n\nIn both jurisdictions, tort law liabilities appear to focus on providing compensation to victims. Safety regulation may be a suitable alternative to tort liability as a means to ensure the safety of medical artificial intelligence systems.\n\n\nData availability\n\nFigshare: Selected English and Taiwanese Judicial Decisions on Tort Liability. https://doi.org/10.6084/m9.figshare.15162339 (Khong, 2021).\n\nThis project contains the following underlying data:\n\n• Dataset.zip (A collection of 10 English and one Taiwanese court cases on tort liability).\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\nAn early version of this paper was presented at the 1st International Conference on Law and Digitalisation 2021 on 21 June 2021. Kind comments and feedback from participants are acknowledged.\n\n\nReferences\n\nAdams ES, Gray MW: Strict liability for the malfunction of a medical expert system. Proceedings of the Annual Symposium on Computer Application in Medical Care. 1987: 93–99.\n\nAllain JS: From Jeopardy! To jaundice: The medical liability implications of Dr. Watson and other artificial intelligence systems. Louisiana Law Review. 2013; 73(3): 1049–1080.\n\nAvanzo M, Trianni A, Botta F, et al.: Artificial intelligence and the medical physicist: Welcome to the machine. Appl. Sci. 2021; 11(4): 1691. Publisher Full Text\n\nBlyth v Birmingham Waterworks Co: 156 ER 1047 (Ex).1856.\n\nBolam v Friern Hospital Management Committee: 1 WLR 582 (QBD).1957.\n\nBolitho v City and Hackney Health Authority: 3 WLR 1151 (HL).1997.\n\nCannataci JA: Liability for medical expert systems: An introduction to the legal implications. Med. Inf. 1989; 14(3): 229–241. Publisher Full Text\n\nCole v Turner: 90 ER 958 (KB).1704.\n\nCollins v Wilcock: 1 WLR 1172 (QBD).1984.\n\nDerry v Peek: 14 App Cas 337 (HL).1889.\n\nDonoghue v Stevenson: AC 562 (HL).1932.\n\nFrank X: Is Watson for oncology per se unreasonably dangerous? Making a case for how to prove products liability based on a flawed artificial intelligence design. Am. J. Law Med. 2019; 45(2–3): 273–294. Publisher Full Text\n\nFroomkin AM, Kerr I, Pineau J: When AIs outperform doctors: Confronting the challenges of a tort-induced over-reliance on machine learning. Ariz. Law Rev. 2019; 61(1): 33–100.\n\nGoudkamp J, Nolan D: Winfield & Jolowicz on tort. (20th ed.). Thomson Reuters; 2020.\n\nHedley Byrne & Co Ltd v Heller & Partners Ltd: AC 465 (HL).1963.\n\nHutchinson T, Duncan N: Defining and describing what we do: Doctrinal legal resarch. Deakin Law Review. 2012; 17(1): 83–120. Publisher Full Text\n\nJabri S: Artificial intelligence and healthcare: Products and procedures. Wischmeyer T, Rademacher T, editors. Regulating artificial intelligence. Springer; 2020; (pp. 307–335). Publisher Full Text\n\nJunod V: Liability for damages caused by AI in medicine: Progress needed. Chappuis C, Winiger B, Editors. Responsabilité Civile Et Nouvelles Technologies. Journée De La Responsabilité Civile 2018. Schulthess; 2019; (pp. 119–149).\n\nKamalnath A: Rethinking liability and licensing for doctors in the era of AI: Insights from company law. Asia Pacific Journal of Health Law & Ethics. 2018; 11(2): 33–50.\n\nKhan F: Medicine in the age of smart machines: Legal liability challenges. Olleros FX, Zhegu M, editors. Research Handbook on Digital Transformations. Edward Elgar Publishing; 2016; (pp. 59–84).\n\nKhong D: Selected English and Taiwanese Judicial Decisions on Tort Liability. figshare. Dataset. 2021. Publisher Full Text\n\nLetang v Cooper: 1 QB 232 (CA).1965.\n\nMacrae C: Governing the safety of artificial intelligence in healthcare. BMJ Qual. Saf. 2019; 28(6): 495–498. PubMed Abstract | Publisher Full Text\n\nMaliha G, Gerke S, Cohen IG, et al.: Artificial intelligence and liability in medicine: Balancing safety and innovation. Milbank Q. 2021; 99: 629–647. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nMeskó B, Görög M: A short guide for medical professionals in the era of artificial intelligence. Npj Digital Medicine. 2020; 3: 126. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMinssen T, Gerke S, Aboy M, et al.: Regulatory responses to medical machine learning. J. Law Biosci. 2020; 7(1): lsaa002. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMolnár-Gábor F: Artificial intelligence in healthcare: Doctors, patients and liabilities. Wischmeyer T, Rademacher T, editors. Regulating artificial intelligence. Springer; 2020; (pp. 337–360). Publisher Full Text\n\nMoor J: The Dartmouth College artificial intelligence conference: The next fifty years. AI Mag. 2006; 27(4): 87–91.\n\nMurali N, Sivakumaran N: Artificial intelligence in healthcare—A review. International Journal of Modern Computation, Information and Communication Technology. 2018; 1(6): 103–110.\n\nNordlinger B, Villani C, Rus D, et al.: Healthcare and artificial intelligence. Springer; 2020.\n\nPesapane F, Suter MB, Codari M, et al.: Regulatory issues for artificial intelligence in radiology. Faintuch J, Faintuch S, editors. Precision Medicine for Investigators, Practitioners and Providers. Elsevier; 2020; (pp. 533–543).\n\nPesapane F, Volonté C, Codari M, et al.: Artificial intelligence as a medical device in radiology: Ethical and regulatory issues in Europe and the United States. Insights Imaging. 2018; 9(5): 745–753. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrice WN, Gerke S, Cohen IG: Potential liability for physicians using artificial intelligence. JAMA. 2019; 322(18): 1765–1766. PubMed Abstract | Publisher Full Text\n\nPrice WN II.: Regulating black-box medicine. Mich. Law Rev. 2017; 116: 421–474. PubMed Abstract\n\nPrice WN II.: Medical malpractice and black-box medicine. Cohen IG, Lynch HF, Vayena E, editors. Big Data, Health Law, and Bioethics. Cambridge University Press; 2018; (pp. 295–306). Publisher Full Text\n\nSmith H, Fotheringham K: Artificial intelligence in clinical decision-making: Rethinking liability. Medical Law International. 2020; 20(3): 131–154. Publisher Full Text\n\nSmith v Bush: 1 AC 831 (HL).1989.\n\nSullivan HR, Schweikart SJ: Are current tort liability doctrines adequate for addressing injury caused by AI?. AMA J. Ethics. 2019; 21(2): E160–E166. PubMed Abstract | Publisher Full Text\n\nTobia K, Nielsen A, Stremitzer A: When does physician use of AI increase liability?. J. Nucl. Med. 2021; 62(1): 17–21. PubMed Abstract | Publisher Full Text\n\nTuring AM: Computing machinery and intelligence. Mind: A Quarterly Review of Psychology and Philosophy. 1950; LIX(236): 433–460. Publisher Full Text\n\nWesterman P: Open or Autonomous: The Debate on Legal Methodology as a Reflection of the Debate on Law. van Hoecke M , editor. Methodologies of Legal Research: What Kind of Method for What Kind of Discipline?. Hart Publishing; 2011; (pp. 87–110).\n\n109,上易,139: 臺灣高等法院民事判決.2020.\n\n吳佳琳: 初探人工智慧的民事法律責任—從歐洲議會機器人民事法律規範建議開展 (A Preliminary Study of the Civil Liability about AI: Focusing on European Parliament resolution of 16 February 2017 with recommendations to the Commission on Civil Law Rules on Robotics). 科技法律透析. 2020; 32(1): 54–70.\n\n吳采薇: 人工智慧醫療器材軟體之監理初探—以美國FDA新監理構想為核心 (A preliminary study of the supervision of artificial intelligence medical device software—Taking the US FDA’s new supervision concept as the core). 科技法律透析. 2020; 32(1): 29–36.\n\n陳鋕雄: 人工智慧醫療決策系統之法律議題 (Legal issues of artificial intelligence medical decision-making systems). 人工智慧與相關法律議題領導護理. 2019; (pp. 1–61). 元照.\n\n陳鋕雄: 智慧醫材臨床應用之法律責任 (The legal liability of the clinical application of medical devices based on artificial intelligence). 領導護理. 2020; 21(3): 1–15."
}
|
[
{
"id": "118385",
"date": "17 Jan 2022",
"name": "Søren Holm",
"expertise": [
"Reviewer Expertise Medical Ethics",
"AI Ethics",
"Regulation of new health technologies"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper by Khong and Yeh compares the legal principles that governs the ascription and allocation of liability to AI systems in clinical medicine in England and in Taiwan. The comparison is interesting, but there seems to be much more emphasis on England than on Taiwan.\nThe legal analysis is, as far as I can ascertain as a non-lawyer sound, but quite descriptive. The authors do not provide any in-depth analysis of the many problems that would arise when trying to make a claim in relation to harm suffered because of problematic AI advice.\nAs is correctly pointed out, most clinical AI systems will not be used directly by patients, but will be used by the health care professionals that interact with the patients, e.g. in the analysis of imaging. This means that the analysis needs to engage with the specific issues that arise in that situation where the AI system is not an agent.\nThe brief outline of the English intentional tort of 'battery', for instance, needs to engage with the question of the relevance of this tort, since non-robotic AI system could never physically touch anyone, and could at the most advise someone else to commit battery.\nAnd, in relation to negligence and product liability we seem first to need an analysis of what it would mean for an AI system to provide the wrong advice, and how that relates to the responsibilities of the producer and the user. At the point where we introduce AI systems in healthcare we do so knowing that they are not perfect, but have a finite error rate. This means that an analysis of product liability cannot rely exclusively on Donoghue v Stephenson since that case was concerned with a product defect that should never happen, i.e., there should never be a decomposed snail in a bottle of root beer.\nThese are just some examples of where the analysis could have been, and arguably need to be deeper.\nI have explored some of these issues in relation to English law with colleagues in an article in Health Care Analysis. 1\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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": "254890",
"date": "30 May 2024",
"name": "Kit Fotheringham",
"expertise": [
"Reviewer Expertise Regulation of AI under the law of England & Wales"
],
"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 propose that harms occurring from defective AI in medicine could be covered by informational torts such as negligent misstatement. Generally, these torts are restricted to cases of \"economic loss\", and the cases cited support this. However, the scenario of harm occurring to patients from defective AI is not a case of economic loss, rather the patient would be able to demonstrate personal injury, and therefore the usual negligence cases (as cited) would apply.\nIf the authors are attempting to make a novel argument that negligent misstatements should also be considered as a valid head of liability, I would expect to see detailed analysis of the law which demonstrates this. As it stands, the section on negligent misstatement could mislead readers who are not familiar with the applicable law.\nThe paragraph on battery could be expanded to give greater detail on why defective AI could be considered a civil trespass to the person.\nThe section on the general law of negligence is satisfactory. However, many of the cites cited are old and dated, whereas more recent caselaw is available and could assist the authors in making more nuanced arguments. For example, the authors should consider the judgement in Montgomery v Lanarkshire Health Board and reflect on the modernised approached to clinical expertise, which replaces Bolam and Bolitho.\nAlthough published after the authors initially submitted their paper, I would recommend that the authors consider Smith and Fotheringham (2022), which explores some of the other torts which could apply in cases of defective AI.\nWhilst I cannot comment on the accuracy of the discussion of the applicable Taiwanese law, for a comparative analysis, I would expect to see more detail directly comparing the various aspects of the rules and norms across the indicated jurisdictions.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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": []
},
{
"id": "275629",
"date": "08 Jun 2024",
"name": "Daria Kim",
"expertise": [
"Reviewer Expertise Innovation and Law"
],
"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 surveys the application of English and Taiwanese tort laws in the context of medical artificial intelligence applications. While this review might be informative for readers not well-versed in the subject, I believe the addressed legal issues require a more detailed analysis. The reference to 'liability from medical artificial intelligence systems' potentially covers many diverse scenarios, making it difficult to assess and validate the authors' legal analysis and conclusions. At face value, the findings appear too generalised, while specific fact patterns could reveal the complexity of applying existing rules to harms arising from AI applications. Calling it a 'comparative study' might be an overstatement, as the respective rules in the two jurisdictions are essentially surveyed in parallel. Comparative legal analysis, which is not explained in the method section, typically involves more than identifying surface-level differences and similarities. The choice of jurisdictions is not explained—is it arbitrary? What have the authors intended to achieve by comparing these particular jurisdictions? Overall, legal issues related to liability for harm caused by the application of AI in medical practice merit a deeper and more nuanced analysis than this paper presents.\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/10-1294
|
https://f1000research.com/articles/10-1293/v1
|
17 Dec 21
|
{
"type": "Review",
"title": "Review of recent lung biomarkers of potential harm/effect for tobacco research",
"authors": [
"Erin Beattie",
"Jeffery Edmiston",
"Patrudu Makena",
"Elizabeth Mason",
"Mike McEwan",
"Krishna Prasad",
"Erin Beattie",
"Jeffery Edmiston",
"Patrudu Makena",
"Mike McEwan",
"Krishna Prasad"
],
"abstract": "Biomarkers of potential harm (BoPH) are indicators of biological perturbations which may contribute to the pathophysiology of disease. In this review, we critically assessed the published data on lung-related BoPH in human lung disease for potential use in evaluating the effects of tobacco and nicotine products. A Scopus literature search was conducted on lung disease biomarkers used in a clinical setting over the last 10 years. We identified 1171 papers which were further screened using commercial software (Sciome SWIFT-Active Screener) giving 68 publications that met our inclusion criteria (data on the association of the biomarker with cigarette smoking, the impact of smoking cessation on the biomarker, and differences between smokers and non-smokers), the majority of which investigated chronic obstructive pulmonary disease. Several physiological and biochemical measures were identified that are potentially relevant for evaluating the impact of tobacco products on lung health. Promising new candidates included blood biomarkers, such as surfactant protein D (SP-D), soluble receptor for advanced glycation end products (sRAGE), skin autofluorescence (SAF), and imaging techniques. These biomarkers may provide insights into lung disease development and progression; however, all require further research and validation to confirm their role in the context of tobacco and nicotine exposure, their time course of development and ability to measure or predict disease progression.",
"keywords": [
"Biomarkers of potential harm",
"Lung biomarkers",
"Tobacco product evaluation",
"Nicotine",
"Lung disease"
],
"content": "Introduction\n\nCigarette smoking causes many different serious lung diseases and the World Health Organization (WHO) estimated 1.5 million worldwide tobacco smoking related premature deaths from chronic respiratory disease in 2017 (World Health Organisation, 2019). Identifying and understanding biomarkers that are early indicators of changes in lung health could play an important role in evaluating the potential for new tobacco products that have a reduced risk of causing tobacco-related disease. Currently, the most prevalent non-cancer respiratory condition caused by tobacco smoking is chronic obstructive pulmonary disease (COPD). COPD is a complex disorder involving both airways and lung parenchyma with airflow limitation that is not fully reversible, generally progressive and accompanied with abnormal inflammatory response (Diaz et al., 2008).\n\nCOPD is generally diagnosed by lung function measurement using spirometry (Graham et al., 2019). Spirometry provides a method of measuring lung physiology that is relatively simple to perform and interpret results (with appropriate training), requires little equipment and is minimally invasive (Gold and Koth, 2016). Spirometry assesses lung function by measuring the volume of air that the patient can expel from the lungs after a maximal inspiration; for example, the forced expiratory volume in one second (FEV1). Expiratory airflow, which is ultimately what is measured in spirometry, is a function of muscular effort, elastic recoil of lungs and thorax, small and large airway function, and interdependence between small airway and the surrounding alveolar attachments (Gold and Koth, 2016).\n\nPatients with suspected obstructive lung disease often present with symptoms such as persistent cough and shortness of breath (Global Initiative for Chronic Obstructive Lung Disease, 2018). Medical history and exposure to other risk factors such as cigarette smoking or air pollution, can assist with a clinical diagnosis. However, the use of spirometry is generally used to confirm a COPD diagnosis. It is a reliable method of differentiating between obstructive airways disorders (e.g. COPD, asthma) and restrictive diseases (in which the size of the lungs is reduced, e.g. fibrotic lung disease).\n\nThe Global Initiative for Obstructive Lung Disease (GOLD) guidelines provide recommendations for the spirometry readout required to confirm a COPD diagnosis and are based upon the FEV1/FVC ratio (Global Initiative for Chronic Obstructive Lung Disease, 2018). This represents the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) as compared to the full, forced vital capacity (FVC). A (FEV1/FVC) readout of less than 0.7 or 70 % is the current threshold to confirm the presence of persistent airflow limitation. Actual versus predicted FEV1 results can then be used to classify the severity or stage of the disease.\n\nHowever, not all individuals presenting with airflow limitation follow the paradigm. On the individual level, spirometry may poorly correlate with symptoms, risk of exacerbation, prognosis and response to treatment in COPD (Salzman, 2012). Several clinical markers and other biomarkers have been proposed for COPD (Gonçalves et al., 2018), however, clinically useful early biomarkers, those that identify pre-symptomatic COPD condition, have yet to be identified. Biomarkers of COPD may be useful in aiding diagnosis, defining specific phenotypes of disease, monitoring exacerbations and evaluating the effects of drugs (Borrill et al., 2008). Biomarkers of COPD may also be useful when evaluating potentially reduced risk tobacco products. The purpose of this narrative review (a project by the CORESTA Biomarker Sub-Group, BMK-161-NWIP) was to examine the recent literature for biomarkers that would be useful in evaluating potential improvements in lung health as smokers switch to potentially reduced risk products. Currently there are few validated biomarkers in this area. The aim was to broadly explore potential biomarkers with specific relevance to lung disease which ranged from spirometry, imaging, to blood and lung sampling.\n\n\nMethods\n\nThe Scopus literature search was conducted in June 2018 included the following parameters: Lung or Pulmonary, and Tobacco or Smok*, and Biomarker or Change* or Difference* or Measur*, and COPD or Emphysema or Bronchitis or Asthma or Obstruct*, and Clinical or Human. It was limited to papers published in English in the last 10 years (from January 1st 2008 to June 14th 2018) and to clinical trials. The search identified 1,171 papers to screen for the review.\n\nA web-based collaborative review software application (SWIFT-Active Screener (Howard et al., 2020)) was used to complete the initial screening of the titles and abstracts of the 1,171 identified papers (manual screening could be used as an alternative to this software). SWIFT-Active Screener uses statistical models to continuously prioritize and estimate relevant papers left to screen. The inclusion criteria were: human studies only, data on the association of cigarette smoking, smoking cessation with the biomarker, and data on smoking versus non-smoking, preferably with data on changes with smoking cessation. Exclusion criteria were: studies of exposure to environmental tobacco smoke, studies of other non-cigarette tobacco products without smoking information, non-lung diseases, genome studies, drug-focused studies, and review articles. Once SWIFT-Active Screener predicted that we had identified 95.8 % of the relevant papers, 322/1,171 papers were screened using a two-reviewer system (i.e., both reviewers agreed the paper should be included for further review, based on the abstract), and finally 68 out of the predicted 71 papers were targeted for further (full-text) screening. Papers were not further filtered according to study quality in order to identify any potential biomarkers that may be of use in the future.\n\nFour potential sources of biomarkers were identified from the included papers: spirometry (lung function), imaging, blood and lung sampling.\n\nAn earlier version of this article can be found on coresta.org (url: https://www.coresta.org/review-recent-lung-biomarkers-potential-harmeffect-tobacco-research-34041.html).\n\n\nResults\n\nOf the papers screened in this study, spirometry was often used to diagnose lung function impairment; 32 of the studies included in this review which investigated non-spirometric markers of lung also included some spirometry data, reflecting the validated status of this technique in detecting changes in the lung and diagnosing COPD. Only a small number of these papers discussed spirometry in the context of lung disease and tobacco, and these are discussed here.\n\nAs noted previously, COPD is a complex and heterogenous disease; not all patients progress at the same rate and the reasons for this heterogeneity are poorly understood. This is clearly observed in the ECLIPSE study, a controlled COPD cohort that included 2,164 clinically stable COPD patients, 245 never smokers and 337 smokers with normal lung function (Agusti et al., 2010). By definition, patients with COPD had airflow limitation, whereas spirometry was normal in the two control groups; clinically stable COPD patients showed significant decreases (p < 0.01) in FEV1 (% predicted) and FEV1/FVC compared to the smoking and non-smoking controls5. Smoking controls also showed a significant reduction in spirometric measures as compared to the non-smoking controls (p < 0.05) (Agusti et al., 2010). The paper also looked at a number of other factors that may indicate the heterogeneity of the disease such as exercise tolerance and reported exacerbations.\n\nDifferences in disease progression were also seen by Lawrence et al. (2017) {Lawrence, 2017 #2997}, who noted that of the 370 COPD patients assessed at baseline and then one year later, patients who declined due to FEV1 change had lower FEV1 at baseline (means 55.7 % vs 67.8 %; p = 0.0023), and larger FEV1 deterioration over 1 year (284 mls vs 44 mls; p = 0.0021), and were more likely to be current smokers (62.5 % vs 10.0 %; p = 0.04) (Lawrence et al., 2017).\n\nThomsen et al. (2014) assessed the relative rather than absolute changes in FEV1 of 3,218 relatively healthy heavy smokers participating in the Danish Lung Cancer Screening Trial (DLCST), a 5-year longitudinal study investigating the effect of screening on lung cancer mortality. Here, the authors reported that when measuring relative changes in FEV1, a significant acceleration of decline was observed in smokers compared to former smokers (smoker vs former smokers: −0.20 % (p = 0.027)), and those with airflow limitation (AFL) compared to those without (AFL vs no AFL: −0.94 % (p < 0.001)) (Thomsen et al., 2014). The authors suggested these factors may speed up the loss of lung function.\n\nIn terms of identifying biomarkers of harm/effect for potential use in evaluation of the effects of tobacco use, a study should track changes in spirometric values as a smoker quits tobacco cigarettes. Within the scope of this aim, only one paper attempted to do this (Drummond et al., 2012). Longitudinal data from the Lung Health Study, a clinical trial of intensive smoking cessation intervention with or without bronchodilator therapy in 5,887 smokers with mild to moderate airflow obstruction were analyzed to determine the association between spirometric measures and 5-year decline in FEV1 and 12-year mortality. When stratifying the study cohort by smoking pattern (either continuous smoker, intermittent quitter or sustained quitter), they found that the association between lower baseline lung function and accelerated decline was present in all three groups, but to a lesser extent in the sustained quitters (Drummond et al., 2012). Intermittent quitters and continuous smokers showed similar patterns when baseline lung function was normal or mildly impaired. However, at levels of more severe baseline lung impairments, they reported that intermittent quitters demonstrated less rapid lung function decline than continuous smokers (Drummond et al., 2012). All smoking patterns showed lung function decline, although this was most accelerated in the continuous smoking group as compared to the intermittent and sustained quitters (Drummond et al., 2012). Never-smokers were not part of this Lung Health Study, thus preventing a more complete comparison to lung function decline in never smokers.\n\nWhile spirometry is considered the gold standard for assessing lung function, it is not without limitations (Global Initiative for Chronic Obstructive Lung Disease, 2018, Andreeva et al., 2017, Perez-Padilla et al., 2015). The technique may not be sensitive enough to detect the condition in asymptomatic patients, such as younger age smokers. There is also poor correlation between spirometry data and other clinical outcomes such as exacerbation frequency (Agusti et al., 2010). Even in patients diagnosed with severe airflow obstruction, not all reported symptoms, exacerbations or showed impaired exercise tolerance, suggesting that FEV1 does not fully capture COPD complexity (Agusti et al., 2010). Therefore, the identification and validation of alternative biomarkers that can be used in the diagnosis, prognosis and treatment of COPD are still required.\n\nOur search yielded nine papers that primarily utilized lung imaging techniques to assess differences in the lungs of smokers and/or respiratory disease patients. Seven of the papers used computed tomography (CT) scans and two used magnetic resonance imaging (MRI) to evaluate the lungs of subjects in the studies. Although spirometry is the primary method used to diagnose lung function impairment, direct imaging of the lungs may add additional sensitivity to the underlying changes in the lung and provide insights into the respiratory disease mechanisms caused by smoking.\n\nCT scans\n\nIn a study by Diaz et al. (2017), quantitative CT measures were used to assess ratios of bronchial lumen and adjacent artery, peak wall attenuation, wall thickness, and wall area percent in 21 smokers with bronchiectasis and 21 never smokers. They demonstrated that these measures could detect differences between the two populations in both affected and unaffected areas of the lungs. Specifically, they identified changes in pulmonary vasculature as a potential mechanism for lung functional changes during bronchiectasis.\n\nBodduluri et al. (2017) used CT measurements of mean lung density at the end of expiration and the end of inspiration in 8,034 subjects of which 103 were lifetime non-smokers. They evaluated the changes in lung regions with normal density and found evidence of gas trapping associated with smoking even in these normal appearing lung regions. The authors concluded that these findings represented mild small airway disease and it was associated with respiratory morbidity. Small airway disease was also investigated by Kirby et al. (2017b) using a similar technique. Inspiratory to expiratory CT measurements were captured and assessed in 133 non-smokers, 97 at risk (former or current smokers), 140 COPD GOLD stage I (early/mild), and 96 COPD GOLD stage II (moderate) patients. The authors assessed two methods for classifying gas trapping; parametric response mapping and a novel disease probability Measure. The two measures performed similarly and could distinguish between at risk populations and GOLD I and GOLD II populations, but the disease probability measure classified more areas as having gas trapping in general and it was the only method that detected more gas trapping in the COPD GOLD II group relative to the COPD GOLD I group. Additional research is needed to understand the differences between these assessment techniques.\n\nVolume adjusted 15th percentile density (PD15) was used by two studies to assess changes in the lung. Shaker et al. (2012) studied 2,052 subjects (893 with airflow obstruction) as part of the Danish Lung Cancer Screening Trial. Increases in PD15 were associated with number of cigarettes per day and pack years in this study. PD15 was also evaluated in a study by Ashraf et al. (2011) and showed similar results with current smokers (n = 548) having higher PD15 scores than former smokers (n = 178). Additionally, this study demonstrated that decreases in PD15 continue for 2 years upon smoking cessation (n = 77). The dose response and reversibility of PD15 indicates it might be helpful in evaluating potentially reduced risk tobacco products. However, the time course for reversal took approximately two years.\n\nOne paper by Smith et al. (2014) investigated spatially matched airway thickness in cigarette smokers with and without COPD. This study demonstrated that spatially matching airways are thinner in the lungs of COPD patients. Previous techniques that do not match for similar airway location may result in comparisons of more proximal airways in COPD patients to more peripheral airways in the control group (Smith et al., 2014). Although this study describes a potential improvement to the assessment technique it did not report any differences due to smoking.\n\nOne study by Kimura et al. (2017) used CT scans of the sinus to investigate the extent of sinusitis and asthma severity in non-smokers (n = 130, < 10 pack years) and smokers (n = 76, ≥ 10 pack years). However, they conducted their analysis separately within each group and did not compare differences between the two populations.\n\nMRI\n\nMRI was used in two identified studies. Alamidi et al. (2016) evaluated resonance relaxation time (T1) in 24 COPD patients (current and former smokers) compared to 12 age-matched control non-smokers. The lung T1 was significantly shorter in the COPD patients and highly correlated with CT density scans and spirometry measurements. Kirby et al. (2017a) used MRI with inhaled noble gas to evaluate ventilation defect percent to assess the lungs of 34 ever-smokers, 48 COPD patients, and 42 never smokers over 30 months. Ventilation defect percent was greater in ever-smokers and COPD patients compared to never smoker controls. The ventilation defect percent also correlated well with spirometry and respiratory questionnaire responses. The authors concluded that “These data strongly support the use of MRI intermediate endpoints in COPD studies.”\n\nLung imaging as an evaluation tool for potentially reduced risk tobacco products is appealing because it allows the visualization of the primarily exposed tissue during cigarette smoking. The imaging techniques are evolving and refinements of the techniques as well as additional data from longitudinal studies will prove useful in the future. The use of current imaging techniques is limited as both CT and MRI systems are expensive and require specialized facilities and training to conduct and interpret the results.\n\nPersistent systemic inflammation is thought to play a significant pathogenic role in COPD (De Martinis et al., 2005). Levels of circulating fibrinogen, C-reactive protein (CRP), interleukins 6 (IL-6) and 8 (IL-8) are biomarkers that have been most often studied in COPD (Agustí et al., 2012).\n\nFibrinogen\n\nFibrinogen is a glycoprotein found in blood, which is converted to fibrin by the enzyme thrombin during tissue and vascular injury leading to fibrin-based blood clots. Elevated levels of fibrinogen have been implicated in cardiovascular disease (Cook and Ubben, 1990). In addition, both CRP and fibrinogen have been associated with the severity of COPD and the risk of cardiovascular disease (van Dijk et al., 2013).\n\nA number of the papers selected through the screening process identified fibrinogen as a potential biomarker for lung disease, especially COPD, with both targeted and untargeted methods being used. Generally, these papers investigated potential biomarkers and their association with severity of COPD or airflow limitation. In the six papers that investigated fibrinogen in COPD patients versus control subjects (made up of current smokers, former smokers and never smokers), elevated levels were found in the COPD groups, irrespective of smoking status (Agustí et al., 2012, Dickens et al., 2011, Merali et al., 2014, York et al., 2010). Devanarayan et al. (2010) and Garcia-Rio et al. (2010) both showed increases in fibrinogen in COPD subjects versus healthy subjects, but these were not significant. However, the Devanarayan et al. (2010) study did identify fibrinogen as one of nine markers capable of distinguishing COPD “rapid decliners” from “slow decliners” . This is supported by the study of Rana et al. (2010) which identified fibrinogen among 33 proteins that were differentially expressed between COPD fast and slow decliners. In addition, both Garcia-Rio et al. (2010) and Dickens et al. (2011) indicated an association between elevated fibrinogen levels and reduced exercise tolerance as measured by the 6-minute walk test.\n\nVery few of the identified papers investigated the effects of smoking on fibrinogen levels. One study by van Dijk et al. (2013) investigating the acute effects of cigarette smoking in COPD patients, showed that fibrinogen levels significantly increased directly after smoking and remained elevated at 35 minutes. While Kalhan et al. (2010) reported a longitudinal study, which followed subjects over 20 years (CARDIA study) and showed that higher fibrinogen was associated with smoking and higher body mass index (BMI). This study also showed an association between higher fibrinogen and 15-year decline in both FVC and FEV1 and that higher levels of fibrinogen at year 7 was associated with greater risk of having abnormal FVC and FEV1 in middle age (Kalhan et al., 2010).\n\nAs these papers generally focused on biomarkers that were associated with COPD once it had been diagnosed, there was scant information on potential early biomarkers associated with COPD development that could be used in the context of potential risk reduction with potentially reduced-risk products (PRRPs). However, the study by Agustí et al. (2012) does show data which indicates a potentially significant increase in levels of fibrinogen in healthy smokers compared with healthy non-smokers, while Dickens et al. (2011) indicate that there was no significant difference between smokers and non-smokers for plasma fibrinogen levels.\n\nIn terms of use of fibrinogen as a biomarker for COPD in PRRP switching studies, Scherer (2018) indicated that it may be a useful marker in larger field studies as power calculations indicate a sample size of a minimum 216 subjects would be required to achieve a statistical difference. This review also estimated that from cessation studies, it would take one year to achieve non-significant levels of fibrinogen in plasma. However, it should be noted that in a cross-sectional analysis, Haswell et al. (2014) noted there was no significant difference in levels of fibrinogen between smokers and never-smokers.\n\nInterleukins\n\nInterleukins are a subset of a larger group of cellular messenger molecules called cytokines, which are modulators of cellular behavior, particularly immune signaling. Like other cytokines, interleukins are produced in response to a stimulus, such as an infectious agent. Increased levels of interleukins in blood serum have been associated with COPD.\n\nThe papers identified through the screening process mainly investigated levels of interleukins in COPD patients and healthy subjects which were both smokers and never smokers using targeted analyses. Of the different interleukins analyzed, IL-6 and IL-8 were the most common. Table 1 shows the levels of IL-6 and IL-8 reported in the papers identified through the screening process for this review.\n\nIQR = interquartile range.\n\nTwo studies identified IL-6 as being significantly higher in subjects with COPD than healthy subjects (Agustí et al., 2012, Dickens et al., 2011), whereas Garcia-Rio et al. (2010) reported IL-6 as not significantly different between COPD patients and healthy subjects after adjustment for gender, age, BMI and pack-years, although there was a significant difference before adjustment. In addition, a study by Hackett et al. (2011) investigating single nucleotide polymorphisms (SNPs) identified a SNP associated with IL-6 that had a significant interaction with cigarette smoking and lung function and that subjects with this SNP would be at risk of developing both COPD and cardiovascular disease. IL-8 was also significantly higher in COPD patients versus healthy subjects in two studies (Dickens et al., 2011, Garcia-Rio et al., 2010). Furthermore, Garcia-Rio et al. (2010) reported that IL-6 and IL-8 were related to severity of COPD and both were inversely related to exercise tolerance as measured by the 6-minute walk test, whereas Agustí et al. (2012) indicated that IL-6 tended to increase with severity of airflow limitation while IL-8 did not.\n\nOther interleukins were reported in the identified publications, but these were only incorporated in single papers. Dickens et al. (2011) investigated levels of IL-12p40, but this showed no significant change between COPD patients and healthy subjects. Devanarayan et al. (2010) studied a number of interleukins in COPD patients and healthy controls. This study showed that IL-4 and IL-7 had the largest increase in the COPD patients versus healthy controls. In addition, a study on elderly subjects in Uppsala, Sweden showed no association between lung function and IL-6 levels, even though this study did show an association between CRP and FEV1 (Kuhlmann et al., 2013).\n\nFew of these studies investigated the levels of interleukins in smokers and non-smokers, however, Agustí et al. (2012) found that IL-8 was higher in smokers versus non-smokers. In concordance with this, Dickens et al. (2011) reported that IL-8 was significantly higher in smokers versus non-smokers, but that IL-6 in smokers was not significantly different compared to non-smokers. A study by Hoonhorst et al. (2014b) investigated the acute effects of smoking three cigarettes in one hour. This study showed an increase in activation of neutrophils in young subjects who were deemed susceptible to COPD, but that levels of IL-6 and IL-8 decreased in older healthy controls, whereas IL-6 decreased significantly in young healthy controls compared with COPD patients.\n\nA review on biomarkers of biological effect by Scherer (2018) also looked at IL-6 for use in PRRP switching studies and identified this marker in blood as having limited suitability for use in field studies. However, for IL-8 there were few studies carried out to investigate this biomarker in this context. In addition, a cross-sectional analysis of smokers versus non-smokers showed that plasma levels for both IL-6 and IL-8 were all below the limit of detection (Haswell et al., 2014).\n\nC-reactive protein\n\nCRP is produced in response to inflammatory conditions such as bacterial, viral and fungal infections and is synthesized in the liver and released into the circulation. It is part of the innate immune system and is associated with the activation of the complement cascade that has been associated with atherosclerosis as well as COPD and asthma (Anderson, 2006, Peisajovich et al., 2008, Thompson et al., 1999).\n\nOf the papers selected through the screening process that investigated plasma biomarkers associated with COPD, eight included CRP through either targeted or untargeted analyses. In most cases, the main objective of these papers was to identify potential biomarkers and their association with COPD disease severity. Of these papers, three identified CRP as being significantly elevated in COPD patients versus healthy subjects (including both smokers and non-smokers) (Agustí et al., 2012, Dickens et al., 2011, Garcia-Rio et al., 2010). In addition, one study using a targeted analysis of plasma CRP on an elderly population of 888 subjects showed CRP and leukocyte count were independently associated with FEV1 (Kuhlmann et al., 2013). Leeming et al. (2017) investigated matrix metalloprotease generated collagen type 1 and type IV fragments (C1M and C6M) to investigate predictors of FEV1 change in COPD patients. This study indicated that C1M and C6M along with CRP and emphysema were significant predictors of lung function decline.\n\nOne study on untargeted analyses on the plasma proteome of COPD patients and matched ex-smokers with no airflow obstruction identified CRP among 31 different proteins that were differentially expressed (Merali et al., 2014). However, two other papers identified through the screening process also looked at untargeted analysis of the plasma proteome of COPD and did not identify CRP as differentially expressed (Rana et al., 2010, York et al., 2010). Of the proteins that were differentially expressed, the majority of these proteins belonged to the complement and coagulation cascades in both studies.\n\nOn the question of the effects of smoking on plasma CRP levels, only two papers addressed the question of the effects of smoking on plasma CRP levels. van Dijk et al. (2013) investigated the acute effects of smoking in a cohort of 31 COPD subjects and showed that CRP increased directly after smoking and returning to normalized levels after 35 minutes. Whereas Kalhan et al. (2010) analyzed plasma samples from a longitudinal study on healthy young adults at time of enrolment over a 20-year period and showed that subjects with higher levels of CRP at year 7 were associated with a greater risk of airflow decline in middle age. A greater risk of having obstructive lung disease by year 20 of the study was noted in subjects that had elevated CRP levels at year 7 and had 10 or more pack years of smoking history.\n\nOther observations from the screened papers were that BMI was associated with CRP (Agustí et al., 2012, Garcia-Rio et al., 2010, Kalhan et al., 2010, Kuhlmann et al., 2013) and that exacerbations in COPD subjects are associated with further elevation of CRP (Dickens et al., 2011).\n\nAs most of the papers are aimed at looking for discriminatory biomarkers for decline in lung function for subjects with COPD, there is little information on how these biomarkers behave in healthy subjects and whether they are predictive of COPD development. A study by Kalhan et al. (2010) does indicate there is a possibility that CRP may be predictive of obstructive lung disease from analysis of CRP levels in young adulthood. However, Scherer (2018) indicated that CRP is less suitable for use in such studies. This is supported by Ogden et al. (2015) and Haswell et al. (2014) which both reported that there was no significant difference between smokers and non-smokers for CRP.\n\nIn addition, CRP is also associated with cardiovascular events and as this affects the cardiovascular system, can potentially be a major confounder for studies investigating effects on the lung from tobacco smoking (Penson et al., 2018, Ridker et al., 2002). In addition, CRP is an acute phase protein produced through microbial infection, and this may also be a confounding source in clinical studies. These challenges may be alleviated through longitudinal studies with large subject numbers, and thus CRP may be relevant for use in longer term studies, such as post-market surveillance.\n\nSP-D\n\nSeveral of the screened publications identified surfactant protein D (SP-D) as a potential biomarker related to the development of COPD. SP-D (43kDa) is a local inflammatory biomarker belonging to the collecting sub-group of the C-type lectin superfamily. The protein can form multimers assembling into trimers and can then form higher multimers such as dodecamers (formed from four trimers) via disulfide crosslinking. It is principally produced in and secreted from type II pneumocytes in the lung and found in alveoli, distal airways and in the blood and plays an important role in regulating immune and inflammatory responses in the lungs (Ito et al., 2015).\n\nGenerally, this biomarker was investigated using targeted analysis and was found to be elevated in the serum of subjects with COPD compared with healthy subjects (Winkler et al., 2011). Dickens et al. (2011) observed that serum SP-D levels were elevated in COPD subjects with unresolved exacerbations and reproducible over a three-month period. Whereas Carolan et al. (2014) found a potential association of SP-D with emphysema and Kim et al. (2012) reported a significant association between SNPs (rs10836312 and rs12793173) and serum SP-D. Contrary to this, Ito et al. (2015) found that total serum SP-D was not significantly different between subjects with smokers with COPD, non-COPD smokers and never smokers. However, this study also investigated fucosylated SP-D in serum and found levels to be significantly higher in COPD patients compared with non-COPD smokers and was directionally higher but not significantly different when compared to never smokers. This study also investigated levels of fucosylated SP-D in non-COPD smokers and never smokers and saw no significant difference between these groups, suggesting fucosylation levels were not affected by smoking status (Ito et al., 2015). Only one other of the screened manuscripts investigated levels of SP-D in smokers and never smokers and this indicated that smoking increased levels of serum SP-D and reduced levels in bronchioalveolar lavage (BAL) fluid from the lungs (Winkler et al., 2011). In addition, Winkler et al. (2011) also found that smoking led to changes in the quaternary structure of SP-D in BAL compared to never smokers with increased levels of these smaller subunits of pulmonary SP-D being found in smokers and subjects with COPD. In support of this, one other publication which was not identified through the screening process, showed that serum SP-D levels were significantly higher in smokers compared to never smokers and former smokers. This study carried out on 756 twin pairs in Denmark also showed there was no significant difference in serum SP-D levels between never smokers and ex-smokers (Johansson et al., 2014).\n\nAGE and RAGE\n\nAccelerated formation and accumulation of advanced glycation end products (AGEs) is believed to occur as a result of oxidative stress and smoking.\n\nAGEs are a heterogeneous and complex group of compounds formed by non-enzymatic glycation and oxidation of proteins and lipids. These AGEs then accumulate in tissues with aging. Furthermore, under oxidative stress and inflammatory conditions their formation and accumulation increase. Examples of AGEs are Nε – (carboxymethyl)-lysine (CML) and Nε – (carboxyethyl)-lysine (CEL) and pentosidine (Hoonhorst et al., 2016).\n\nThe receptor for AGE (RAGE) is an immunoglobulin family member that is highly expressed in human lung (Carolan et al., 2014). It has been associated with several inflammatory diseases such as diabetes mellitus, cardiovascular and respiratory diseases (Carpagnano et al., 2016, Kim et al., 2012). This membrane bound protein can bind to AGE, triggering inflammatory responses, oxidative stress, and RAGE over-expression (Hoonhorst et al., 2016).\n\nIn addition, there is a soluble form of RAGE (sRAGE) which can be found in the circulation and is believed to act as a decoy receptor for clearance of circulating AGEs, preventing ligation of membrane bound RAGE and therefore may act as a ‘protective’ mechanism (Cheng et al., 2013, Hoonhorst et al., 2016).\n\nIn the three manuscripts that investigate AGEs and RAGEs there was a consensus that levels of sRAGE decrease in COPD patients compared to healthy controls (Carolan et al., 2014, Cheng et al., 2013, Hoonhorst et al., 2016). Both Carolan et al. (2014) and Cheng et al. (2013) indicated that sRAGE was negatively associated with severity of emphysema, whereas Hoonhorst et al. (2016) indicated sRAGE was lower in GOLD stage III (Severe COPD) patients compared to GOLD stage I.\n\nOnly Hoonhorst et al. (2016) investigated the levels of AGEs in the circulation and concluded that levels of CML and CEL were comparable in COPD and healthy subjects after adjustment for confounding variables.\n\nFor comparisons between smokers and non-smokers, Hoonhorst et al. (2016) showed higher levels of pentosidine in young healthy never smokers compared to young healthy smokers. However, this is reversed in old healthy never smokers compared to old healthy smokers. In the case of plasma sRAGE levels, there appears to be higher levels in both young and healthy never smokers compared to the smoker cohorts, but this was not significant. This is supported by Cheng et al. (2013) who found there was no significant difference between sRAGE levels in smokers versus non-smokers and no association with pack years of smoking.\n\nInterestingly, AGEs have been shown to accumulate differently in body compartments and has been shown to accumulate in the skin but not plasma, sputum or bronchial biopsies. This accumulation in skin can be measured by skin autofluorescence (SAF) (Hoonhorst et al., 2014a, Hoonhorst et al., 2016).\n\nAlthough not a plasma biomarker, SAF was found at higher levels along with lower plasma sRAGE and this was associated with decreased lung function (Hoonhorst et al., 2014a). In addition, this study shows higher SAF values in both old and young smokers compared to old and young never smokers (Hoonhorst et al., 2016). Another study reported by Hoonhorst et al. (2014a) also showed that with smoking history, a higher number of pack-years smoking was associated with higher SAF levels in the young and old healthy groups analysed. In addition, it showed that within the old healthy subjects, current smoking was associated with higher SAF levels. This is in agreement with a further study carried out by Isami et al. (2018) which shows that SAF was also correlated to pack year history of smoking. It should be noted that in subjects with cardiovascular disease and diabetes SAF levels were significantly higher than those without (Hoonhorst et al., 2014a), and this should be a consideration for this biomarker if applied in clinical studies.\n\nAs previously discussed, COPD is a complex disorder involving both airways and lung parenchyma with airflow limitation that is not fully reversible, generally progressive and accompanied with abnormal inflammatory response (Diaz et al., 2008). COPD is generally diagnosed by lung function measurement using spirometry, but not all individuals presenting with airflow limitation follow the paradigm. On the individual level, spirometry may poorly correlate with symptoms, risk of exacerbation, prognosis and response to treatment in COPD. Several clinical markers and other biomarkers have been proposed for COPD (Gonçalves et al., 2018), however, clinically useful early biomarkers that identify pre-symptomatic COPD condition have yet to be identified. Biomarkers of COPD may be useful in aiding diagnosis, defining specific phenotypes of disease, monitoring exacerbations and evaluating the effects of drugs (Borrill et al., 2008).\n\nA variety of pathological changes at different locations of the lung were reported in COPD. Increased numbers of macrophages and CD8 T lymphocytes were observed in proximal airways (>2mm), peripheral airways (<2mm), lung parenchyma and pulmonary vasculature (MacNee, 2005). Goblet cell and squamous cell metaplasia is detected with mucus hyper secretion in both proximal and peripheral airways (Ramos et al., 2014). Enlarged smooth muscle and connective tissue, altered ciliary function, and increased neutrophils and lymphocytes infiltration of bronchial glands are observed in proximal airways. In the peripheral airways, an early-stage bronchiolitis with luminal and inflammatory exudates, peribranchial fibrosis and airway narrowing is noticed (MacNee, 2006). Alveolar wall destruction from loss of epithelial and endothelial cells and abnormal enlargement of airspaces distal to terminal bronchioles with micro- and macroscopic emphysematous changes are key pathological features observed in lung parenchyma (MacNee, 2006). In pulmonary vasculature, intimal thickening, endothelial dysfunction is seen in early stage and hypertrophy of vascular smooth muscle, collagen deposition, destruction of capillary bed, development of pulmonary hypertension and cor pulmonale are observed in late stage (MacNee, 2006).\n\nThere is an urgent need for discovery and validation of reliable disease biomarkers to better characterize the phenotypic heterogeneity and the prognosis of COPD. To that end, early measurable changes in molecular, cellular, structural or functional level are the important targets for biomarker development. These alterations progressively accumulate and contribute to the pathophysiology and eventually to the adverse disease outcomes. Therefore, collection and processing of high-quality biological specimens from different locations of the lung are critical to the development of COPD biomarkers. This section will focus on some of the COPD biomarkers from lung specific samples, 1) induced sputum, 2) bronchial biopsies, 3) bronchoalveolar lavage fluid, 4) exhaled breath condensate, 5) exhaled breath temperature, and present results from selected publications.\n\nInduced sputum\n\nA number of studies have suggested a pathogenetic role for airway inflammation in the induction of both chronic sputum production and chronic airflow obstruction in smokers (Pauwels, 2001). Sputum originates from both proximal and distal airways, which can be induced by inhalation of hypertonic saline. Induction of sputum is a safe, reliable, and relatively non-invasive method. Induced sputum provides information about both inflammatory cells and mediators present in the airways, potentially relevant for phenotypic characterization of COPD and asthma. Induced sputum differs from spontaneous sputum by having a higher number of viable cells and less squamous cell contamination (Pauwels, 2001). Several sputum induction methods were previously described (Efthimiadis et al., 2002, Paggiaro et al., 2002, Pavord et al., 1997, Scheicher et al., 2003, Weiszhar and Horvath, 2013). The few limitations of this sample type include 1) the difficulty in obtaining healthy control samples, 2) the lack of general standardization, and 3) the presence of highly charged mucins that require usage of detergents which may interfere with some of the biomarkers of interest (Woolhouse et al., 2002). Several COPD biomarkers in induced sputum were previously described (Barnes et al., 2006, Comandini et al., 2009, Iwamoto et al., 2014, Keatings and Barnes, 1997, Kleniewska et al., 2016, Rutgers et al., 2000).\n\nTitz et al. (2015) compared proteomic and transcriptomic changes in the sputum of asymptomatic smokers, COPD smokers, former smokers, and never smokers. In this study, smokers exhibited the proteomic and transcriptomic changes in mucin/trefoil proteins and a prominent xenobiotic/oxidative stress response. Proteomic analysis revealed that TIMP1, APOA1, C6orf58, and BPIFB1 (LPLUNC1), KRT19, PPIB, TF, AHSG, SERPINC1, AFM, ALB, HRG, and CNDP1 are differentially abundant proteins between the COPD and the asymptomatic smoker group. Aldehyde dehydrogenase 3A1 (ALDH3A1) showed the strongest and most significant increase in the asymptomatic and COPD smokers compared to non-smokers and former smokers (Table 2). In this study, except S100A6, there were no differentially expressed transcripts between the former smoker and never smoker groups (Titz et al., 2015).\n\nCOPD = chronic obstructive pulmonary disease; SP-D = surfactant protein D; EBT = exhaled breath temperature.\n\nNicholas et al. (2010) used a proteomic approach to compare novel noninvasive biomarkers using induced sputum in GOLD stage 2 COPD and healthy smoker control subjects. In this study, the authors used a sequential approach of identifying 1,325 individual protein spots in which 37 were quantitatively and 3 qualitatively different between the two groups. Using this approach, apolipoprotein A1 and lipocalin-1 were potential biomarkers and reduced in patients with COPD when compared with healthy smokers (Table 2). Immunohistochemistry revealed that these two markers were localized to bronchial mucosa (Nicholas et al., 2010). Hoonhorst et al. (2016) assessed the association of AGEs and sRAGE in plasma, sputum, bronchial biopsies, and skin and found no differences in sputum sRAGE between smokers and COPD groups.\n\nBronchial biopsies\n\nBronchial biopsy is an invasive sample collection technique and specimens obtained by bronchoscopy provide a very useful tool to study cellular, immunological and molecular abnormalities of the airway mucosa (Azzawi et al., 1990, Beasley et al., 1989, Elston et al., 2004). Bronchial biopsies have been useful for documenting the structural changes, cellular patterns, and expression of inflammatory proteins in patients with COPD (Barnes et al., 2006). An accurate method of analysis for endobronchial biopsies in health and disease was previously described in the literature (Jeffery et al., 2003). The advantage of bronchial biopsies is that they represent airway tissue, maintaining the spatial relationships of structural components that may be important to functional changes (Jeffery et al., 2003). Bronchial biopsies can be cultured and used for ex vivo evaluations to assess their responses to experimental treatments. However, due to the invasive nature of the sample collection, it is difficult to recruit subjects in clinical trials. The biopsy of proximal airways may not closely reflect all the pathologic changes present in peripheral airways and lung parenchyma, which are the sites responsible for airflow limitation in COPD (Barnes et al., 2006).\n\nThe selected papers on bronchial biopsies or lung tissue evaluated several biomarkers of effect.\n\nKunz et al. (2013) compared several potential markers, including elastic fibers; proteoglycans (versican, decorin); collagens type I and III in bronchial biopsies after 30-months of inhaled steroids treatment or placebo in COPD current and ex-smokers. This study shows that there is no significant difference in the selected biomarkers in current and ex-smokers with COPD (Kunz et al., 2013). Freeman et al. (2013) evaluated subsets of specific TLRs on lung CD8+ T cells, CD4+ T cells, CD56+ NK cells, IFN-g, and TNFα by CD8+ T cells in lung tissues of healthy smokers and COPD smokers. In this study, the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 and only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells was significantly increased in COPD subjects relative to those without COPD (Freeman et al., 2013). In separate experiments, IFN-g and TNFα release significantly increased CD8+ T cells of COPD smokers when co-stimulation by Pam3CSK4, a specific TLR2/1 ligand.\n\nBronchoalveolar lavage fluid\n\nBronchoalveolar lavage (BAL), performed during flexible bronchoscopy, has gained widespread acceptance and provides important information about immunologic, inflammatory, and infectious processes taking place at the alveolar level (Meyer et al., 2012). BAL is an invasive procedure in which a bronchoscope with light and a small camera is passed through the mouth or nose into the lungs and epithelial lining fluid is collected by flushing into a small part of the lung and then recollected for examination. A flexible bronchoscope is longer and thinner than a rigid bronchoscope. Flexible bronchoscopy is more common than rigid bronchoscopy, and flexible bronchoscopy usually does not require general anesthesia and contains a fiberoptic system that transmits an image from the tip of the instrument to an eyepiece or video camera at the opposite end (Mehta et al., 2018). Generally, BAL has been performed safely on patients with stable COPD (Paradis et al., 2016). However, it is unsafe to perform BAL on patients with moderate/severe lung disease, or during acute exacerbations (Louhelainen et al., 2008). One of the limitations of BAL collection in COPD patients is often inadequate and not representative of the situation in the bronchioles due to airway collapse and reduced fluid recovery (Barnes et al., 2006).\n\nBAL is the most common clinical procedure to sample the components of the pulmonary airways. BAL samples can be analyzed for cytological, hematologic, biochemical, and microbiological examination. A variety of lung specific biomarkers can be evaluated in BAL including surfactant proteins (Barnes et al., 2006, Dahl, 2008, Hartl and Griese, 2006, Moré et al., 2010, Winkler et al., 2011), proinflammatory cytokines (Barnes, 2008, Barnes, 2009), inflammatory responses/cells (Löfdahl et al., 2006, O'Donnell et al., 2006, Rovina et al., 2013, Wang et al., 2018, Wen et al., 2010), matrix metalloproteins (Molet et al., 2005, Ostridge et al., 2016, Papakonstantinou et al., 2015), ‘omic’ markers (including proteomic, metabolomic and microRNA) (Adamko et al., 2015, Chen et al., 2010, Cruickshank-Quinn et al., 2017, Fujii et al., 2017, Molina-Pinelo et al., 2014, Tu et al., 2014, Wendt et al., 2016), and oxidative stress markers (Drost et al., 2005, Morrison et al., 1999).\n\nSome of the selected papers in this review compared biomarkers in smokers, non-smokers and COPD smokers in BAL and the majority of them were inflammatory markers. Röpcke et al. (2012) analyzed a large panel of markers in bronchoalveolar lavage, bronchial biopsies, serum and induced sputum of healthy smokers and COPD smokers (GOLD II). Samples were collected twice within a period of 6 weeks and over 100 different markers were validated for the respective matrices prior to analysis. Several biomarkers were reported, including total cell counts, CD14+ monocytes, α1-antitripsin, EGFR, HAS, TIMP1, calprotectin, and IL-8 in BAL and α1-antitripsin, HAS and MMP3 in induced sputum. (Holz et al., 2014) reported that potential prognostic value of biomarkers in BALF, sputum and serum in a five-year clinical follow-up of smokers with and without COPD. The lung function decline was larger in smoking COPD patients than in healthy smokers. This study demonstrated that higher levels of BAL or induced sputum markers, IL-8, calprotectin or, MMPs (neutrophilic airway inflammation markers) in the baseline were associated with a larger decline in lung function over a 5-year period. Winkler et al. (2011) compared BAL and serum SP-D in young and elderly smokers, COPD smokers and non-smokers. SP-D levels decreased in an order of young, smokers, and COPD smokers compared to non-smokers.\n\nExhaled Breath\n\nCondensate. Collection of exhaled breath condensate (EBC) for sampling the lower airways involves tidal breathing into a chilled collection device where water vapor in exhaled breath is condensed. EBC unlike BAL, is a noninvasive, inexpensive, and easy to collect method and repeat without causing airway injury or inflammation (Kharitonov and Barnes, 2002, Mutlu et al., 2001, O'Reilly and Bailey, 2007) and has the potential for screening and diagnosis of COPD, especially during exacerbations and treatment response monitoring (Borrill et al., 2008, Holz, 2005). Several COPD biomarkers in EBC were reported, including pH (Borrill et al., 2005, Kostikas et al., 2002), prostaglandins (Antczak et al., 2012, Montuschi et al., 2003), oxidative stress markers (Dekhuijzen et al., 1996, Nowak et al., 1999), proinflammatory cytokines (Bucchioni et al., 2003, He et al., 2014, Lin et al., 2017, Liu et al., 2014), and matrix metalloproteinases (Hao et al., 2019, Mercer et al., 2005).\n\nTemperature. Exhaled breath temperature (EBT), a component of exhaled breath, is regarded as a promising noninvasive diagnostic tool to evaluate respiratory and other diseases (Popov, 2011). Most studies on EBT have been performed in asthmatic patients to assess changes in the degree of airway inflammation (Paredi et al., 2002, Piacentini et al., 2002, Piacentini et al., 2007). Some studies also evaluated EBT as a potential biomarker in smoking and COPD (Carpagnano et al., 2016, Hoffmeyer et al., 2009, Lázár et al., 2014, Popov et al., 2017, Vrbica et al., 2017).\n\nThe selected paper described EBT as a novel and early biomarker of COPD in the pre-symptomatic stage (Labor et al., 2016). In a two year follow up study, Labor and coworkers evaluated EBT and lung function markers in smokers with no prior diagnosis of COPD until the subjects developed COPD (GOLD 1) (Labor et al., 2016). This study demonstrated a change in EBT after smoking a cigarette at an initial visit was significantly predictive for disease progression. Carpagnano et al. (2016) showed the sensitivity of EBT to cigarette smoke and the potential to predict future development of COPD in current smokers.\n\n\nDiscussion\n\nSeveral prospective biomarkers of potential harm have been described in the last decade, including molecular, cellular, structural and functional endpoints that are implicated in different stages of COPD with or without exacerbations. Clinically relevant early biomarkers of pre-symptomatic COPD would be important for early diagnosis and effective treatment. In this review, potential biomarkers for future validation and key limitations were identified from the 68 publications that met our preset criteria and were subdivided into 4 categories based on the technique and location of sample type (spirometry, imaging, blood and lung sampling).\n\nSpirometry is widely accepted as the gold standard for assessing lung function and diagnosis of COPD. However, it has some limitations, for example an accurate result depends on collective and active participation from both the subject and the operator. In addition, the technique may lack the required sensitivity to detect the condition in asymptomatic patients, such as healthy smokers. There is also poor correlation between spirometry data and clinical outcomes such as exacerbation frequency. Even in patients diagnosed with severe airflow obstruction, not all reported symptoms and exacerbations show impaired exercise tolerance, suggesting that FEV1 does not fully capture COPD complexity. Therefore, the development and validation of alternative biomarkers that can be used in the diagnosis, prognosis and treatment of COPD are still required.\n\nUnderstanding of the pathophysiological mechanisms in COPD is growing with the utility of improved imaging tools that are now more widely available. Advanced imaging techniques allow thorough anatomical, structural and functional abnormalities to be acquired in vivo. In combination, the acquired imaging data demonstrate a remarkable degree of regional variation in lung function. Different imaging modalities vary significantly in terms of temporal and spatial resolution, and each has its own advantages and disadvantages. The major limitation of ionizing radiation exposure is being overcome by new technologies, which reduce radiation dose while enhancing image quality. However, the utility of current imaging techniques is limited as both CT and MRI systems are expensive and require specialized facilities and training to conduct and interpret the results. Lung imaging as an evolving tool for the assessment of potentially reduced risk tobacco products is appealing because it allows the visualization of the primarily exposed tissue during cigarette smoking. The imaging techniques are evolving and refinements of the techniques as well as additional data from longitudinal studies will prove useful in the future. These modalities are likely to become increasingly important in early diagnosis of COPD.\n\nBlood biomarkers associated with the development of smoking-related lung disease have been a major area of research. However, as these biomarkers may come from other organs in the body and not necessarily the lungs, this creates a level of difficulty in interpreting their specific association with lung disease. In addition, most of these papers investigated blood biomarkers in patients with COPD with a view to identifying biomarkers that could be indicative of disease progression. Nevertheless, these studies present little evidence to establish the utility of these biomarkers in demonstrating the potential for reduced risk of lung disease if a subject switches from tobacco cigarettes to a PRRP.\n\nOf the blood biomarkers reviewed here, only IL-8 was reported as significantly higher in smokers versus non-smokers; IL-6, sRAGE and SP-D levels showed some promise, but may require a larger sample size to differentiate between smokers and non-smokers. These biomarkers may have potential for use in PRRP switching studies, however further research is required to investigate their utility for use in this context. In addition, further understanding of the role these biomarkers may play in the pathological changes involved in the development of COPD would be required. Fibrinogen and CRP show conflicting data on comparisons between smokers and non-smokers and may be confounded by other factors such as BMI. Finally, although not a plasma biomarker, SAF warrants further investigation as the available evidence, whilst limited, shows some promise in its utility for use in potential reduced risk tobacco product studies context.\n\nSeveral pathophysiological alterations at different locations of the lung were reported in all stages of COPD. The selected papers in lung sampling yielded several biomarkers that were previously well described; for example: IL-8, α1-Antitrypsin, Apolipoprotein A1, and MUC5AC. Novel biomarkers that were identified include AGER, RAGE, SP-D and exhaled breath temperature. Interestingly, RAGE, SP-D and IL-8 in lung sampling are also found in plasma. Therefore, validation of these biomarkers would provide additional confidence. However, obtaining lung sample quality and consistency in COPD subjects is a difficult task. Development and validation of noninvasive techniques such as measuring exhaled breath condensate and temperature would be useful for local biomarker readouts.\n\n\nConclusion\n\nOverall, in the past decade, researchers have identified many potential biomarkers of smoking related lung diseases, including COPD. The existing tools such as spirometry may not address all the current gaps, while other cutting-edge imaging tools are rapidly developing and promising for the identification of novel biomarkers. This review identified existing and new biomarkers that have potential for being predictive biomarkers in smokers and COPD subjects, as well as provide insights into disease development and progression. All these identified biomarkers require further development and fit-for-purpose assessments including validation of the biomarkers in tobacco and nicotine context and understanding their potential role in the development of disease.\n\n\nData availability\n\nNo data are associated with this article.",
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Publisher Full Text\n\nMehta AC, Hood KL, Schwarz Y, et al.: The Evolutional History of Electromagnetic Navigation Bronchoscopy: State of the Art. Chest. 2018; 154: 935–947. PubMed Abstract | Publisher Full Text\n\nMerali S, Barrero CA, Bowler RP, et al.: Analysis of the plasma proteome in COPD: Novel low abundance proteins reflect the severity of lung remodeling. COPD. 2014; 11: 177–189. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMercer PF, Shute JK, Bhowmik A, et al.: MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir. Res. 2005; 6: 151. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeyer KC, Raghu G, Baughman RP, et al.: An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am. J. Respir. Crit. Care Med. 2012; 185: 1004–1014. PubMed Abstract | Publisher Full Text\n\nMolet S, Belleguic C, Lena H, et al.: Increase in macrophage elastase (MMP-12) in lungs from patients with chronic obstructive pulmonary disease. Inflamm. Res. 2005; 54: 31–36. PubMed Abstract | Publisher Full Text\n\nMolina-Pinelo S, Pastor MD, Suarez R, et al.: MicroRNA clusters: dysregulation in lung adenocarcinoma and COPD. Eur. Respir. J. 2014; 43: 1740–1749. Publisher Full Text\n\nMontuschi P, Kharitonov SA, Ciabattoni G, et al.: Exhaled leukotrienes and prostaglandins in COPD. Thorax. 2003; 58: 585–588. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoré JM, Voelker DR, Silveira LJ, et al.: Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease. BMC Pulm. Med. 2010; 10: 53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorrison D, Rahman I, Lannan S, et al.: Epithelial permeability, inflammation, and oxidant stress in the air spaces of smokers. Am. J. Respir. Crit. Care Med. 1999; 159: 473–479. PubMed Abstract | Publisher Full Text\n\nMutlu GM, Garey KW, Robbins RA, et al.: Collection and analysis of exhaled breath condensate in humans. Am. J. Respir. Crit. Care Med. 2001; 164: 731–737. PubMed Abstract | Publisher Full Text\n\nNicholas BL, Skipp P, Barton S, et al.: Identification of lipocalin and apolipoprotein A1 as biomarkers of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2010; 181: 1049–1060. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNowak D, Kasielski M, Antczak A, et al.: Increased content of thiobarbituric acid-reactive substances and hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking. Respir. Med. 1999; 93: 389–396. PubMed Abstract | Publisher Full Text\n\nO'donnell R, Breen D, Wilson S, et al.: Inflammatory cells in the airways in COPD. Thorax. 2006; 61: 448–454. 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Publisher Full Text\n\nPavord ID, Pizzichini MM, Pizzichini E, et al.: The use of induced sputum to investigate airway inflammation. Thorax. 1997; 52: 498–501. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPeisajovich A, Marnell L, Mold C, et al.: C-reactive protein at the interface between innate immunity and inflammation. Expert. Rev. Clin. Immunol. 2008; 4: 379–390. PubMed Abstract | Publisher Full Text\n\nPenson PE, Long DL, Howard G, et al.: Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study. Eur. Heart J. 2018; 39: 3641–3653. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPerez-Padilla R, Wehrmeister FC, Montes De Oca M, et al.: Instability in the COPD diagnosis upon repeat testing vary with the definition of COPD. PLoS One. 2015; 10: e0121832. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPiacentini GL, Bodini A, Zerman L, et al.: Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma. Eur. Respir. J. 2002; 20: 108–111. Publisher Full Text\n\nPiacentini GL, Peroni D, Crestani E, et al.: Exhaled air temperature in asthma: methods and relationship with markers of disease. Clin. Exp. Allergy. 2007; 37: 415–419. PubMed Abstract | Publisher Full Text\n\nPopov TA: Human exhaled breath analysis. Ann. Allergy Asthma Immunol. 2011; 106: 451–456; quiz 457. Publisher Full Text\n\nPopov TA, Kralimarkova TZ, Labor M, et al.: The added value of exhaled breath temperature in respiratory medicine. J. Breath Res. 2017; 11: 034001. PubMed Abstract | Publisher Full Text\n\nRamos FL, Krahnke JS, Kim V: Clinical issues of mucus accumulation in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2014; 9: 139–150. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRana GS, York TP, Edmiston JS, et al.: Proteomic biomarkers in plasma that differentiate rapid and slow decline in lung function in adult cigarette smokers with chronic obstructive pulmonary disease (COPD). Anal. Bioanal. Chem. 2010; 397: 1809–1819. PubMed Abstract | Publisher Full Text\n\nRidker PM, Rifai N, Rose L, et al.: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 2002; 347: 1557–1565. Publisher Full Text\n\nRöpcke S, Holz O, Lauer G, et al.: Repeatability of and relationship between potential COPD biomarkers in bronchoalveolar lavage, bronchial biopsies, serum, and induced sputum. PLoS One. 2012; 7: e46207. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRovina N, Koutsoukou A, Koulouris NG: Inflammation and immune response in COPD: where do we stand?. Mediat. Inflamm. 2013; 2013: 413735.\n\nRutgers SR, Timens W, Kaufmann HF, et al.: Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur. Respir. J. 2000; 15: 109–115. Publisher Full Text\n\nSalzman SH: Which Pulmonary Function Tests Best Differentiate Between COPD Phenotypes?. Respir. Care. 2012; 57: 50–60. PubMed Abstract | Publisher Full Text\n\nScheicher ME, Terra Filho J, Vianna EO: Sputum induction: review of literature and proposal for a protocol. Sao Paulo Med. J. 2003; 121: 213–219. PubMed Abstract | Publisher Full Text\n\nScherer G: Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: A literature review. Regul. Toxicol. Pharmacol. 2018; 94: 203–233. PubMed Abstract | Publisher Full Text\n\nShaker SB, Dirksen A, Lo P, et al.: Factors influencing the decline in lung density in a Danish lung cancer screening cohort. Eur. Respir. J. 2012; 40: 1142–1148. Publisher Full Text\n\nSmith BM, Hoffman EA, Rabinowitz D, et al.: Comparison of spatially matched airways reveals thinner airway walls in COPD. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study and the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax. 2014; 69: 987–996. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThompson D, Pepys MB, Wood SP: The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. 1999; 7: 169–177. PubMed Abstract | Publisher Full Text\n\nThomsen LH, Dirksen A, Shaker SB, et al.: Analysis of FEV1 decline in relatively healthy heavy smokers: implications of expressing changes in FEV1 in relative terms. COPD. 2014; 11: 96–104. PubMed Abstract | Publisher Full Text\n\nTitz B, Sewer A, Schneider T, et al.: Alterations in the sputum proteome and transcriptome in smokers and early-stage COPD subjects. J. Proteome. 2015; 128: 306–320. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nWeiszhar Z, Horvath I: Induced sputum analysis: step by step. Breathe. 2013; 9: 300–306. Publisher Full Text\n\nWen Y, Reid DW, Zhang D, et al.: Assessment of airway inflammation using sputum, BAL, and endobronchial biopsies in current and ex-smokers with established COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2010; 5: 327–334. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWendt CH, Nelsestuen G, Harvey S, et al.: Peptides in Bronchoalveolar Lavage in Chronic Obstructive Pulmonary Disease. PLoS One. 2016; 11: e0155724. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWinkler C, Atochina-Vasserman EN, Holz O, et al.: Comprehensive characterisation of pulmonary and serum surfactant protein D in COPD. Respir. Res. 2011; 12: 29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWoolhouse IS, Bayley DL, Stockley RA: Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax. 2002; 57: 667–671. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organisation: WHO highlights huge scale of tobacco-related lung disease deaths. World Health Organisation; 2019.\n\nYork TP, Van Den Oord EJ, Langston TB, et al.: High-resolution mass spectrometry proteomics for the identification of candidate plasma protein biomarkers for chronic obstructive pulmonary disease. Biomarkers. 2010; 15: 367–377. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "123253",
"date": "25 Feb 2022",
"name": "Sabina Antonela Antoniu",
"expertise": [
"Reviewer Expertise Clinical Pulmonary 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\nThe purpose of this narrative review is probably to discuss biomarkers of tobacco-induced harm which have \"pathogenic\" value, i.e. are indicative of a \"pre-clinical\" disease. I use probably because the title is unclear and could read better if lung biomarkers would be replaced by biomarkers only, given that blood derived biomarkers are also considered.\nOther major issues:\n\nThe focus is on COPD although this is not reflected by the title. The consideration of this disease is indeed appropriate but it would be better if also reflected in the title (given the topic is a really \"hot\" one).\n\nThe biomarkers cannot be considered as diagnostic tests. You mention spirometry biomarkers, imaging biomarkers or blood/lung biomarkers. The biomarker should be the variable in itself. Furthermore, instead of spirometry biomarkers functional biomarkers would read better. Imaging is appropriate. Instead of blood and lung biologic would read better.\n\nDiscussion of functional biomarkers does not include biomarkers of small airways and/or lung parenchyma (the latter by the way measured in a more reliable way with other tests than spirometry).\n\nDiscussion is not too focused nor too practical but this is probably due the lack of statistical analysis (meta analysis).\n\nIf you want to also consider the value of these biomarkers in monitoring disease progression and you want to use COPD as index disease, this would be a very valuable review. Actually most of the data review falls in this category.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": []
},
{
"id": "123252",
"date": "18 Mar 2022",
"name": "Isaac Kirubakaran Sundar",
"expertise": [],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis review is focused on analyzing existing literature on COPD biomarkers of potential harm emphasizing its impact on tobacco products and lung health outcomes. Without integrating data from the potential of reduced-risk tobacco product studies, the authors’ claim that these findings from COPD biomarkers will benefit tobacco product research are not valid. It will be important for the authors to keep the focus of this review based on known biomarkers of COPD and smoking-related lung disease.\nMajor Comments:\n\nFraming this in the title/abstract as an unbiased review evaluating BoPH for use in general tobacco research seems inaccurate when the literature search used to select articles explicitly required one of the lung disease-associated words “COPD or Emphysema or Bronchitis or Asthma or Obstruct”. Much of the text focuses explicitly on biomarkers of COPD and in some cases the intersection of smoking and COPD, but there is not much discussion of biomarkers that differ with tobacco use specifically.\n\nIn terms of BoPH associated with tobacco use itself, the biomarkers discussed do not give a complete picture. This could be improved by widening the search criteria mentioned above or changing the text to reflect the clear COPD/lung disease focus of this review.\n\nMany of the findings mentioned in this review do not include significance values, and several do not even mention whether the findings were significant. Subject numbers are also missing from several findings. Data tables summarizing findings are not present for several sections. Adding more actual results/statistical significance will make this article much more useful.\n\nThe one table that includes statistical values for biomarkers does not include any direct comparisons between smokers and non-smokers.\n\nDetails about study designs could be explained (in the text or in summary tables) to improve clarity (i.e., defining terms such as “sustained quitters”, “ever-smokers”, etc.).\n\nIncluding a separate section on epigenomic biomarkers (i.e., DNA methylation) from peripheral blood, lung tissues, and other sample types if any. Additionally, novel circulating biomarkers (extracellular vesicles/exosomes) and their contents (miRNAs and proteins) affected in smokers and COPD compared to non-smokers will be important to consider. This would be an important area where more research is needed for the identification of early biomarkers of lung disease as well as identifying potential for a reduced-risk tobacco product. The limitations in biomarker literature should be clearly defined and how to overcome this in future studies should be discussed later in the review before the conclusion section.\n\nMost of the biomarker studies compiled/discussed in this review seem to be very old (> 10 years). It is not clear if there are no new studies that replicated the prior findings in a larger cohort that were not included based on a thorough literature search.\n\nUnable to find any reference from 2020-2022 regarding COPD biomarkers. Relatively fewer references are included from 2016 to 2019. Authors should avoid citations of the article describing the basic procedures and reviews. The purpose of a review is to update the current literature in light of their focused review of the literature. Please refrain from citing older review articles and try to give importance to original research articles under appropriate sections.\n\nThere is a lack of coherence and integration of findings in chronological order for specific sample types described under each section. This should be carefully addressed during the revision.\nMinor Comments:\nImportant keywords appear to be misspelled in the first paragraph of the brief methods section and should be corrected for clarity (“Smok*” and “Measur*”).\n\nAdditionally, what do asterisks after keywords imply? This is unclear in the text.\n\nThere are a few typos e.g., “Peribranchial” which need to be checked and corrected.\n\nSometimes, the study details were provided without mentioning the key findings from the study. i.e., (Kimura et al. 2017) described in the CT scan section.\n\nAny insight on imaging findings from modified risk tobacco products will be important to include and discuss based on current literature.\n\nThe sample type used for analysis is not indicated when the findings are described (Rana et al., 2010).\n\nThe biomarker is a single word, not “bio-marker”.\n\nFormat the table with missing information (sample size for all the citations should be included). Additionally, the comments section should be labelled as ‘Key Findings’ and the reference citation can be moved to the last column. The title of table 1 should include COPD. This table should not mention general biomarkers and include only COPD-related studies.\n\nIncluding schematic figures based on identified COPD biomarkers from different sample types based on current literature summarized in this review would be informative to readers who are new to this field.\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? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1293
|
https://f1000research.com/articles/10-924/v1
|
15 Sep 21
|
{
"type": "Clinical Practice Article",
"title": "Strychnine poisoning due to traditional Chinese medicine: a case series",
"authors": [
"Hok-Fung Tong",
"Candace Yim Chan",
"Sau-Wah Ng",
"Tony Wing-Lai Mak",
"Hok-Fung Tong",
"Candace Yim Chan",
"Sau-Wah Ng"
],
"abstract": "Background: Strychnine poisoning is rare but possibly fatal. The most reported sources of strychnine poisoning include rodenticides and adulterated street heroin. Here we report a case series of an unusual cause of strychnine poisoning – Strychni semen, a herb known as “maqianzi” in traditional Chinese medicine (TCM). Methods: All cases of strychnine poisoning confirmed by the Hospital Authority Toxicology Reference Laboratory (HATRL, the highest-level clinical toxicology laboratory in Hong Kong) between May 2005 and May 2018 were reviewed. Results: Twelve cases of strychnine poisoning were recorded, and Strychni semen was the exclusive source. Ten (83.3%) patients presented with muscle spasms, and four (33.3%) developed typical conscious convulsions. The poisoning was severe in two (16.7%) patients, moderate in three (25%) and mild in eight (58.3%). No case fatality was recorded. Three (25%) patients were TCM practitioners and two (16.7%) were laymen who bought the herb themselves without a proper prescription. Conclusion: The practice of TCM is becoming popular in different parts of the world amid the COVID-19 pandemic. The spectrum of clinical features of strychnine poisoning secondary to Strychni semen are similar to those arising from different origins. Eliciting a history of TCM use, apart from exposure to rodenticides and drugs of abuse, may allow timely diagnosis in patients with compatible clinical features. Enhancement of TCM safety could minimize the hazard.",
"keywords": [
"Strychnine poisoning",
"herbal medicine poisoning",
"Strychni semen",
"Maqianzi"
],
"content": "Background\n\nAround a century ago, the wide availability of strychnine as an over-the-counter remedy for a variety of ailments caused a significant number of deaths, especially in children1. As such, strychnine has been withdrawn from the food and medicine markets in many countries, and poisoning is now rare. Nowadays, the most reported sources of poisoning include rodenticides2,3 and adulterated street heroin4,5, where strychnine was added to increase the heroin retention when it volatized6.\n\nStrychni semen, a herb also known as “maqianzi” in traditional Chinese medicine (TCM), also contains strychnine together with its less toxic analog, brucine. The herb is used for its analgesic, anti-diarrheal, antioxidant, anti-inflammatory, anti-microbial and anti-neoplastic properties7,8. However, it has an apparently narrow therapeutic index – the recommended dosage is 0.3–0.6 g daily according to the Chinese Pharmacopoeia 20159.\n\nStrychnine is rapidly absorbed from the gastrointestinal tract and toxicity may occur as soon as 15 minutes after ingestion. By inhibition of glycine receptors at the spinal cord, strychnine overdose causes weakness and intermittent spasms. Each episode of spasm lasts for around half to two minutes and is easily triggered by emotional distress or even trivial sensory stimuli10. Severe spasms may mimic epileptic convulsions, but there is preserved awareness without post-ictal drowsiness. This typical feature of strychnine poisoning is known as conscious convulsions/spinal seizures11 and may mimic tetanus, though the latter can be differentiated by a positive history of injury, and a more gradual and protracted course of illness12. Severe convulsions may cause rhabdomyolysis and can be rapidly fatal due to respiratory failure13. Milder symptoms of strychnine poisoning include agitation, palpitations, hyperventilation, dizziness, hyperacusis and paresthesia14.\n\nApart from epilepsy and tetanus, acute dystonia and hypocalcemia are the other differential diagnoses of strychnine poisoning. In acute dystonia, muscle contractions are more static. Hypocalcemia also results in numbness and muscle spasms but can be easily differentiated by blood tests15.\n\nManagement of strychnine poisoning is supportive. Activated charcoal may be given if patients present early. Benzodiazepines are used to control muscle spasms, and a dark and quiet environment also helps. Airway intervention and mechanical ventilation can be lifesaving, though succinylcholine must be avoided as it exacerbates muscle spasms15–17.\n\nHere we report a case series of an unusual cause of strychnine poisoning – Strychni semen.\n\n\nMethods\n\nAll cases of strychnine poisoning, which were analytically confirmed by the Hospital Authority Toxicology Reference Laboratory (HATRL), between May 2005 and May 2018 were reviewed. HATRL is the highest-level clinical toxicology laboratory serving all public hospitals in Hong Kong, and analysis of suspected herbal poisoning is one of the unique services provided by the laboratory. Clinical records were reviewed to collect the patient demographics, details of exposure, clinical features, pertinent laboratory findings, treatment provided and clinical outcomes.\n\nDiagnosis of strychnine poisoning was confirmed by detection of strychnine in urine, and Strychni semen exposure was inferred by the concurrent detection of brucine. Detection of strychnine and brucine was performed by using high-performance liquid chromatography with diode array detection (HPLC-DAD; Agilent 1100 and 1200 LC Systems with DAD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS; Agilent 1100 LC System with Applied Biosystems 4000 QTrap triple-quadruple mass spectrometer)18. Wherever available, herbal prescriptions were transcribed and studied, unused herbs were morphologically identified, and analysis of strychnine and brucine was performed on suspicious herbal products.\n\n\nResults\n\nThere were twelve cases of strychnine poisoning confirmed during the study period, and all of them were due to Strychni semen (Table 1). Two severe cases are further described to highlight the salient features.\n\nA 55-year-old male (case 5 in Table 1), a TCM practitioner, was woken up by severe wrist pain at night and inadvertently took 19 grams (31 times the recommended therapeutic dosage) of Strychni semen instead of another herb. He developed dizziness, hyperventilation, generalized muscle spasms and conscious convulsions 30 minutes later. He attended the accident & emergency department and was hospitalized. Activated charcoal and intravenous diazepam (3 mg) were given, and the symptoms subsided six hours later. However, there was rhabdomyolysis (plasma creatine kinase level 5085 U/L; reference interval 45–235 U/L) and he required prolonged aggressive rehydration. Strychni semen exposure was confirmed by detection of both strychnine and brucine in urine. He eventually recovered and was discharged after one week of admission.\n\n*: Severe poisoning (see text for description)\n\na: Recurrent episodes of poisoning\n\nb: This patient was a TCM practitioner\n\nc: This patient was a layman who bought the herb from a TCM pharmacy\n\n+: Present\n\n-: Absent\n\nA 45-year-old man (case 7 in Table 1) consulted a bone setter for gouty arthritis and was dispensed some herbal powder with undisclosed ingredients. One hour after taking the herbal powder, he developed chest discomfort, dyspnea, hyperacusis, generalized muscle spasms, trismus, opisthotonus and conscious convulsions. He was hospitalized and repeated dosing of intravenous diazepam (10 mg in total) was required to control the convulsions. The symptoms lasted for seven hours, but he soon requested early discharge despite medical advice. Strychni semen exposure was subsequently analytically confirmed.\n\nThe demographics and clinical features of all 12 patients are summarized in Table 1 in chronological order of presentation. Numbers of male and female patients were equal. The median age was 48.5 years (range 8 – 58 years). Strychni semen exposure was the exclusive source of strychnine poisoning, and the herb was most commonly used to relieve chronic pain. Four (33.3%) patients had recurrent episodes of poisoning before the definite diagnosis was made. Ten (83.3%) patients presented with muscle spasms, and four (33.3%) patients developed typical conscious convulsions. One patient (case 10) had transient respiratory acidosis, which resolved spontaneously. Median latent period before symptom onset was 0.5 hours (range 0.2 – 2 hours), and the median symptom duration was 3.5 hours (range 0.5 – 7 hours). Based on a previously published poisoning severity score system19, the poisoning was severe in two (16.7%) patients, moderate in three (25%) and mild in seven (58.3%). No case fatality was recorded, and all patients recovered eventually.\n\nIntriguingly, three (25%) patients were professional TCM practitioners (cases 2, 4, 5) themselves. On the other hand, two (16.7%) were laymen who bought Strychni semen without a proper prescription. One was a housewife (case 8) who bought the herb at a Chinese medicine pharmacy and took a markedly excessive dose (15 times the recommended dosage) of Strychni semen based on a misprinted soup recipe in a book borrowed from a public library20.\n\n\nDiscussion\n\nOur results showed that Strychni semen was the exclusive source of clinically and analytically confirmed strychnine poisoning in Hong Kong during the 14-year study period. In addition, Strychni semen poisoning shared a similar spectrum of clinical features with strychnine poisoning due to other causes1,10,11,15,16,21. This peculiarly predominant source of strychnine poisoning in Hong Kong is likely contributed to by the fact that most Hong Kong residents are ethnic Chinese.\n\nNevertheless, with globalization, immigration and the rising popularity of TCM around the world22, especially amid the COVID-19 pandemic23, eliciting a history of herbal medicine use, in addition to exposure to rodenticides and drugs of abuse, may be helpful in making the clinical diagnosis of strychnine poisoning. Identifying the source of strychnine poisoning is also important for public health measures.\n\nUnfortunately, obtaining a definite history of Strychni semen use can be challenging if the herbal prescription is not disclosed by the TCM practitioner. In our case series, five (41.6%) patients did not possess such information, which made the diagnosis difficult. We believe that empowering patients in the therapeutic process by disclosing the herbal prescription can only be beneficial, as the value of this safety enhancement step has been unquestionably exemplified by Western medicine professionals for decades. We noted that TCM clinics associated with the Hospital Authority and the universities in Hong Kong provide computer-generated herbal prescriptions to their patients. However, this good practice is neither universally exercised nor required legally.\n\nIntriguingly, three patients of our case series were TCM practitioners themselves, who were the learned professionals of this dangerous herb. This illustrates the fact that Strychni semen is a dangerous herb and systematic measures should be introduced to minimize such poisoning events.\n\nEnhancement in TCM dispensing could be an important measure. Among our case series, the TCM dispensers did not prevent the inappropriate dosages of Strychni semen from being prescribed by the TCM practitioners. Shockingly, Strychni semen was dispensed to two patients (case 1 & 8) who did not bear a registered TCM practitioner’s prescription. These suboptimal practices should certainly be noted and enhanced by the profession. To ensure patient safety, both good prescription and dispensing practices are essential. In the long run, all TCM practitioners and dispensers around the world should be adequately trained, certified and licensed.\n\n\nConclusion\n\nThe practice of TCM is becoming popular in different parts of the world amid the COVID-19 pandemic. This study serves to remind the profession that strychnine poisoning can result from TCM use. The spectrum of clinical features of strychnine poisoning secondary to Strychni semen (maqianzi) are similar to those that arise from different origins. Eliciting a history of TCM use, apart from exposure to rodenticides and drugs of abuse, may allow timely diagnosis in patients with compatible clinical features. Enhancement of TCM safety could minimize the hazard.\n\n\nConsent\n\nWe respected all patients’ rights to privacy and protected their identity. The study was approved by the Kowloon West Cluster Research Ethics Committee of the Hospital Authority, Hong Kong (approval number KW/EX-19-002), who waived the need for informed consent as the presented data have been anonymized and de-identified.",
"appendix": "References\n\nAikman J: Strychnine Poisoning in Children. J Am Med Assoc. 1930; 95(22): 1661–5. Publisher Full Text\n\nCantrell FL: Look What I Found! Poison Hunting on eBay®. Clin Toxicol (Phila). 2005; 43(5): 375–9. PubMed Abstract | Publisher Full Text\n\nLindsey T, O’Hara J, Irvine R, et al.: Strychnine Overdose Following Ingestion of Gopher Bait. J Anal Toxicol. 2004; 28(2): 135–7. PubMed Abstract | Publisher Full Text\n\nDecker WJ, Baker HE, Tamulinas SH: Two deaths resulting from apparent parenteral injection of strychnine. Vet Hum Toxicol. 1982; 24(2): 86. PubMed Abstract\n\nO’Callaghan WG, Joyce N, Counihan HE, et al.: Unusual strychnine poisoning and its treatment: report of eight cases. Br Med J (Clin Res Ed). 1982; 285(6340): 478. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCole C, Jones L, McVeigh J, et al.: Adulterants in illicit drugs: a review of empirical evidence. Drug Test Anal. 2011; 3(2): 89–96. PubMed Abstract | Publisher Full Text\n\nPatel K, Laloo D, Singh GK, et al.: A review on medicinal uses, analytical techniques and pharmacological activities of Strychnos nux-vomica Linn.: A concise report. Chin J Integr Med. 2017; 1–13. PubMed Abstract | Publisher Full Text\n\nGuo R, Wang T, Zhou G, et al.: Botany, Phytochemistry, Pharmacology and Toxicity of Strychnos nux-vomica L.: A Review. Am J Chin Med. 2018; 46(1): 1–23. PubMed Abstract | Publisher Full Text\n\nState Pharmacopoeia Commision: Pharmacopoeia of the People’s Republic of China 2015. 1st ed. Beijing, China: China Medical Science Press; 2015. Reference Source\n\nOberpaur B, Donoso A, Clavería C, et al.: Strychnine poisoning: an uncommon intoxication in children. Pediatr Emerg Care. 1999; 15(4): 264–5. PubMed Abstract\n\nFlood RG: Strychnine poisoning. Pediatr Emerg Care. 1999; 15(4): 286–7. PubMed Abstract\n\nPhilippe G, Angenot L, Tits M, et al.: About the toxicity of some Strychnos species and their alkaloids. Toxicon. 2004; 44(4): 405–16. PubMed Abstract | Publisher Full Text\n\nHeiser JM, Daya MR, Magnussen AR, et al.: Massive strychnine intoxication: Serial blood levels in a fatal case. Clin Toxicol. 1992; 30(2): 269–83. PubMed Abstract | Publisher Full Text\n\nCaspary DM, Pazara KE, Ko¨ssl M, et al.: Strychnine alters the fusiform cell output from the dorsal cochlear nucleus. Brain Res. 1987; 417(2): 273–82. Publisher Full Text\n\nNelson L, Hoffman R, Howland MA, et al.: Goldfrank’s Toxicologic Emergencies. Eleventh Edition. 11th Edition. New York: McGraw-Hill Education / Medical; 2019. Reference Source\n\nJackson G, Ng SH, Diggle GE, et al.: Strychnine poisoning treated successfully with diazepam. Br Med J. 1971; 3(5773): 519–20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLambert JR, Byrick RJ, Hammeke MD: Management of acute strychnine poisoning. Can Med Assoc J. 1981; 124(10): 1268–70. PubMed Abstract | Free Full Text\n\nNg SW, Ching CK, Chan AYW, et al.: Simultaneous detection of 22 toxic plant alkaloids (aconitum alkaloids, solanaceous tropane alkaloids, sophora alkaloids, strychnos alkaloids and colchicine) in human urine and herbal samples using liquid chromatography–tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2013; 942–943: 63–9. PubMed Abstract | Publisher Full Text\n\nPersson HE, Sjöberg GK, Haines JA, et al.: Poisoning Severity Score. Grading of Acute Poisoning. J Toxicol Clin Toxicol. 1998; 36(3): 205–13. PubMed Abstract | Publisher Full Text\n\nChong YK, Ching CK, Ng SW, et al.: Recipes and general herbal formulae in books: causes of herbal poisoning. Hong Kong Med J. 2014; 20(4): 343–6. PubMed Abstract | Publisher Full Text\n\nKatz J, Prescott K, Woolf AD: Strychnine poisoning from a Cambodian traditional remedy. Am J Emerg Med. 1996; 14(5): 475–7. PubMed Abstract | Publisher Full Text\n\nCyranoski D: THE BIG PUSH FOR CHINESE MEDICINE. Nature. 2018; 561: 448–50.\n\nRen J, Zhang AH, Wang XJ: Traditional Chinese medicine for COVID-19 treatment. Pharmacol Res. 2020; 155: 104743. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "94448",
"date": "29 Sep 2021",
"name": "Jou-Fang Deng",
"expertise": [
"Reviewer Expertise Medical toxicologist"
],
"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 am a medical toxicologist having been in practice since 1982. Many years ago, I used to treat severe convulsion cases related to events of drug abuse, which ended up with a diagnosis of strychnine poisoning confirmed by a clinical toxicology laboratory. However, strychnine poisoning related to the use of traditional medicine is not what I am familiar with, and as it is described in the article, it indeed may potentially occur in our society, in which the practice of traditional medicine is not well regulated.\n\nStrychnine poisoning could be a life-threatening condition, and without appropriate treatment and timely ventilation support, life can disappear quickly. This article has brought up some important points, relevant to both the societies of traditional medicine and western medicine. Since strychnine itself does possess prominent toxicity, to prevent any unnecessary and avoidable poisoning, I would like to propose that the dispensing of strychnine contented herbs should not continue, given its toxic potential.\n\nThis article describes a retrospective study of a collection of unusual cases of strychnine poisoning which need to be remembered in general practice as well as emergency settings. This is a very interesting clinical report and is valuable for the clinical doctors. Since it is a well written article, and clearly demonstrates the importance of the history of herb intake in our daily practice, I would recommend that there is no need for any revision.\n\nIs the background of the cases’ history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the conclusion balanced and justified on the basis of the findings? Yes",
"responses": []
},
{
"id": "101016",
"date": "06 Dec 2021",
"name": "Camille Paradis",
"expertise": [
"Reviewer Expertise Pharmacy",
"Clinical Toxicology"
],
"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 retrospective case series. This work is very interesting since it presents a circumstance of exposure to strychnine by therapeutic error, which is unusual compared to the numerous cases of intoxication in the context of suicidal behavior or other involuntary circumstances. This has implications for the management of intoxicated patients because this circumstance does not raise suspicion of this type of xenobiotic.\nFor the context, I find that the reason for the use of strychnine as a heroin adulterant is not easy to understand. If it is difficult to explain it quickly, perhaps it would be better to just mention this use, without detailing its origin. The bibliographic reference can remain the same. Secondly, I did not really understand why the term \"weakness\" was used for the description of strychnine poisoning. Classically, patients present with a state of hyperexcitability with significant rigidity, perhaps you meant to refer to the symptom \"coma\" by this term? If you change it, consider doing so in Table 1 as well.\nRegarding the data shared on your case series, do you have any notion of the amounts of strychnine and brucine found in the urine of your patients? If you have them, it would be a pity not to share them, especially to compare them with the rest of the literature. In addition, it might be interesting to provide the dates of each case of intoxication, perhaps in your table. Actually, you indicate that the use of TCM is increasing, it might be interesting to see how the number of intoxications evolve over the duration of your study.\nFor the discussion, I really have trouble seeing how you conclude that Strychni semen poisonings are the only circumstances of strychnine poisonings in your study location. It is possible that you have other arguments for stating this, but they need to be included in your paper. In particular, you should explicitly state that no center other than HATRL can analytically confirm strychnine poisoning in your study location. In a recently published study by Paradis et al., 1 it is shown that cases of strychnine poisoning still occur through old rodenticide products. Then I find the sentence that starts with \"We believe that empowering patients...\" perhaps a bit long and I find it difficult to easily understand its purpose.\nFinally, two formal remarks. On the bibliography, you specify \"Clin Toxicol (Phila)\" (2) and \"Clin Toxicol\" alone (13), check that there is not a clarification to be made on which one is alone. For the expression of all your values as a percentage, it seems to me that for a number of patients <100 you should express your values as integers and not as decimal numbers.\nFor the conclusion, I find it perfectly appropriate with a clear purpose, its opening is particularly valid.\n\nIs the background of the cases’ 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 conclusion balanced and justified on the basis of the findings? Yes",
"responses": [
{
"c_id": "7561",
"date": "13 Dec 2021",
"name": "Hok Fung Tong",
"role": "Author Response",
"response": "Thank you very much for your comments and suggestions on improving the quality of the manuscript. Please kindly find below our responses. 1) For context, I find that the reason for the use of strychnine as a heroin adulterant is not easy to understand. If it is difficult to explain it quickly, perhaps it would be better to just mention this use, without detailing its origin. The bibliographic reference can remain the same. - The reason has been removed. 2) I did not really understand why the term \"weakness\" was used for the description of strychnine poisoning. Classically, patients present with a state of hyperexcitability with significant rigidity, perhaps you meant to refer to the symptom \"coma\" by this term? If you change it, consider doing so in Table 1 as well. - We replaced the term “weakness” with “stiffness” instead as this should be the more appropriate description, although some patients would describe such symptom as “weak”. 3) Regarding the data shared on your case series, do you have any notion of the amounts of strychnine and brucine found in the urine of your patients? If you have them, it would be a pity not to share them, especially to compare them with the rest of the literature. - Our laboratory did not provide quantitative analyses of strychnine and brucine. Therefore, such information is not available. 4) In addition, it might be interesting to provide the dates of each case of intoxication, perhaps in your table. Actually, you indicate that the use of TCM is increasing, it might be interesting to see how the number of intoxications evolve over the duration of your study. - We have added the years of clinical presentation in Table 1. 5) For the discussion, I really have trouble seeing how you conclude that Strychni semen poisonings are the only circumstances of strychnine poisonings in your study location. It is possible that you have other arguments for stating this, but they need to be included in your paper. In particular, you should explicitly state that no center other than HATRL can analytically confirm strychnine poisoning in your study location. - Being the highest level clinical toxicology laboratory in Hong Kong, HATRL is the only laboratory which provides analytical confirmation for strychnine poisoning locally. For all analytically confirmed strychnine poisoning cases that we have encountered during the study period, they were all due to Strychni semen. Such information is now stated in the methods section. 6) In a recently published study by Paradis et al., it is shown that cases of strychnine poisoning still occur through old rodenticide products. - We agree that strychnine poisoning can still occur through rodenticides, and have added the citation of this study in the introduction section. 7) Then I find the sentence that starts with \"We believe that empowering patients...\" perhaps a bit long and I find it difficult to easily understand its purpose. - We have removed the sentence. 8) Finally, two formal remarks. On the bibliography, you specify \"Clin Toxicol (Phila)\" (2) and \"Clin Toxicol\" alone (13), check that there is not a clarification to be made on which one is alone. For the expression of all your values as a percentage, it seems to me that for a number of patients <100 you should express your values as integers and not as decimal numbers. - We have unified the references as “Clin Toxicol”, and have modified the percentages accordingly."
}
]
}
] | 1
|
https://f1000research.com/articles/10-924
|
https://f1000research.com/articles/10-961/v1
|
23 Sep 21
|
{
"type": "Research Article",
"title": "A whole genome atlas of 81 Psilocybe genomes as a resource for psilocybin production.",
"authors": [
"Kevin McKernan",
"Liam Kane",
"Yvonne Helbert",
"Lei Zhang",
"Nathan Houde",
"Stephen McLaughlin",
"Liam Kane",
"Yvonne Helbert",
"Lei Zhang",
"Nathan Houde",
"Stephen McLaughlin"
],
"abstract": "The Psilocybe genus is well known for the synthesis of valuable psychoactive compounds such as Psilocybin, Psilocin, Baeocystin and Aeruginascin. The ubiquity of Psilocybin synthesis in Psilocybe has been attributed to a horizontal gene transfer mechanism of a ~20Kb gene cassette. A recently published highly contiguous reference genome derived from long read single molecule sequencing has underscored interesting variation in this Psilocybin synthesis gene cassette. This reference genome has also enabled the shotgun sequencing of spores from many Psilocybe strains to better catalog the genomic diversity in the Psilocybin synthesis pathway. Here we present the de novo assembly of genomes of 81 Psilocybe genomes compared to the P.envy reference genome. Surprisingly, the genomes of Psilocybe galindoi, Psilocybe tampanensis and Psilocybe azurescens lack sequence coverage over the previously described Psilocybin synthesis pathway but do demonstrate amino acid sequence homology to an alternative pathway and may illuminate previously proposed convergent evolution of Psilocybin synthesis.",
"keywords": [
"Psilocybe cubensis",
"Genome",
"Single molecule sequencing",
"Psilocybin"
],
"content": "Introduction\n\nPsilocybin has recently been awarded breakthrough drug status by the FDA (Tullis 2021). Psilocybin has also been shown to be a safe alternative to traditional selective serotonin re-uptake inhibitors (SSRIs) for the treatment of depression (Griffiths et al. 2016; Ross et al. 2016; Bogenschutz et al. 2018; Carhart-Harris et al. 2021; Davis et al. 2021). SSRIs have also been shown to be effective at reducing SARs-CoV-2 viral load (Schloer et al. 2020; Creeden et al. 2021; Dechaumes et al. 2021; Schloer et al. 2021; Zimniak et al. 2021). The mechanism of the viral interference is hypothesized to be related to the co-expression of ACE2 and DOPA decarboxylase (DDC) which catalyzes the synthesis of serotonin (Attademo and Bernardini 2021). It is possible psilocybin’s serotonin agonism will show promise in COViD treatment and prevention in the future, thus understanding the biological mechanism of synthesis is of increasing importance.\n\nTwo models have been proposed for psilocybin production in Psilocybe spp. Horizontal gene transfer has been thoroughly described by Reynolds et al. and Fricke et al., while convergent evolution has been proposed by Awan (Fricke et al. 2017; Awan 2018; Reynolds et al. 2018). Given the broad geographic distribution of psilocybin-producing mushrooms and the history of human cultivation and selection for psilocybin-producing strains, these models may not be mutually exclusive.\n\nTo address this question, we whole-genome sequenced 81 Psilocybe spp. spore samples to assess the sequence coverage over the previously well-characterized psilocybin synthesis cassette.\n\n\nResults\n\nIn a whole-genome sequencing survey of 81 Psilocybe spp. genomes we noticed a lack of sequence coverage over the psilocybin gene cluster described by Reynolds et al. for five of the 81 Psilocybin producing genomes (three Psilocybe tampanensis, one Psilocybe galindoi, one Psilocybe azurescens). These genomes also exhibited genome-wide poor read mapping efficiency to the Psilocybe cubensis “P.envy” reference genome, with the exception of the mitochondria and ITS regions. These non-conical psilocybin-synthesizing genomes share 99%, 100%, and 91% ITS sequence identity to a Psilocybe tampanensis sequence described by Rockefeller et al. (NCBI accession number: MH220315.1). The sequence from Rockefeller et al. was obtained in the wild and verified with photography of morphological features. The sequences described in this study were derived from spores that can be legally sold for taxonomy purposes but cannot be legally cultured to obtain morphological or chemical verification.\n\nOne other genus was labelled as Panaeolus copelandia but delivered two 100% identical ITS sequence to Psilocybe cubensis and Aspergillus fumigatus. This samples was omitted from further analysis. Sequencing and variant calling statistics are displayed in Figure 1 and Supplement Table 1.\n\n(Left) Photographs of strains were obtained from the vendors public websites. (Middle Left). Sequence coverage of all contigs larger than 1 kb where coverage is on the Log Y axis and contigs sorted by length (largest to smallest: left to right) are on the X axis. (Middle Right) Assembly statistics from Quast 5.0. (Right Top) Number of Heterozygous and Homozygous SNPs detected with reads mapped to the P. cubensis “P.envy” reference. (Right Bottom) Number of Reads for each run according to Samtools flagstat.\n\nDespite the low read mapping rates for Psilocybe tampanensis, Psilocybe galindoi and Psilocybe azurescens, the de novo assemblies of these genomes have high BUSCO completeness scores (93%) and matching ITS sequences suggesting they are indeed Psilocybe but differ enough at the species level to produce low cross species read mapping rates.\n\nAn alternative hypothesis is that these libraries are metagenomic or contaminated with non-Psilocybe spp. fungi but still provide enough sequence coverage of the ITS region due to its high copy number. Contaminated libraries are usually detectable with bimodal sequencing coverage as its rare for the organisms to be equimolar. All five non-P. cubensis species have very uniform sequence coverage across the contigs and high BUSCO completion scores with strong ITS sequence implying clean assemblies.\n\nIn combination, these data demonstrate close relatedness of Psilocybe tampanensis and Psilocybe galindoi but distant relatedness to the Psilocybe cubensis “P.envy” reference genome. Given the known psilocybin production in these alternative Psilocybe species, these data also imply an alternative synthesis pathway must exist in these species as suggested by Awan.\n\nUniform sequence coverage and high read mapping rates were observed over most of the of P. cubensis “P.envy” genome for most of the strains (50 of the 81 are displayed in Figure 2 and Figure 3). A few notable higher coverage exceptions were the ITS region on Scaffold_9 and the mitochondrial genome represented by Scaffold_26. This is not a surprising result given the increased copy number of ITS and mitochondrial sequences in fungal genomes.\n\nDue to size limitations, only 50 genomes are presented. The remaining read mapping results can be seen in the underlying data.\n\nScaffolds labeled with a T have a single ~200 bp terminal telomeric sequence. Scaffolds with TT have telomeric sequence on both ends and are assumed to be tip to tip telomeric chromosomes. Scaffolds are ordered from largest to smallest from left to right. P. azurascens (OR-Coast) has low mapping frequency due to divergence.\n\nA few smaller, repeat-rich contigs (scaffolds 27-31) demonstrated more variable coverage across the Psilocybe genus. The ITS region on Scaffold_9 appears to be a tandem repeat which is collapsed in the reference sequence. Scaffolds 27, 28, 31, and 32 have telomeric ends and are small (171 kb, 117 kb, 69 kb, 33 kb). While these smaller contigs have variable coverage in Psilocybe spp., it is important to understand that they represent less than 2% of the genome. Scaffolds 29 and 30 lack telomeric sequence and are 74 kb and 69 kb respectively. Three scaffolds have telomeric sequences on both ends. (Scaffold_2: 4.3 Mb, Scaffold_3: 4.1 Mb; Scaffold_9: 2.3 Mb) suggesting these are tip-to-tip chromosome assemblies.\n\nThe genomes most diverged from the P. cubensis “P.envy” reference genome (P. tampanensis, P. galindoi, P. azurescens) exhibited very low read mapping rates. This is demonstrated by P. azurescens (OR-Coast) in Figure 3. This genome-wide low mapping rate was also observed in the psilocybin production cassette on Scaffold_7 (Figure 4 and Figure 5).\n\nIntegrated Genome Viewer (IGV) coverage plot over the psilocybin synthesis pathway described by Reynolds et al. Strains Huautla and Mazatapec have complete sequence coverage while P. azurescens is lacking sequencing coverage over most of the genes.\n\nLow coverage genomes of the same strain (Costa Rica and Samui) were summed together. Bottom- IGV view of three strains with close homology to the reference genome.\n\nDespite the low read mapping rates to P. cubensis “P.envy”, P. tampanensis assembled into 23 kb N50 genome with a 93% BUSCO completeness score and a 99% identical match to Rockefeller et al. ITS sequence for P. tampanensis. These low mapping rates are reflective of a highly diverged species at the nucleotide level but to exhaust the exploration of psilocybin production, amino acid level homology was further explored.\n\nTo search for pathway redundancy, we utilized tBLASTn to identify alternative psilocybin-producing enzymes in the reference P. cubensis “P.envy” genome. PsiK exists in the conical cluster on scaffold_7 but also has a close homolog on scaffold_1. The copy in the conical cluster on scaffold_7 has a unique SnpEFF high impact variant at p.Arg173Gly that only exists in P. cubensis “P.envy” (Figure 6B). The copy on Scaffold_1 is missing the 5′ exon in P. tampanensis, P. galindoi and P. azurenscens, and is significantly diverged. The most closely related Scaffold_7 PsiK amino acid sequences are seen in a multiple sequence alignment seen in Figure 6A. Further cloning and expression is required to confirm if this additional copy provides any pathway redundancy. Of interest, these alternative alignments are only partially clustered with PsiM and often PsiM is located in the middle of 80 kb contigs in the absence of other pathway related genes (Table 1). This demonstrates a non-clustered psilocybin synthesis pathway in the non-P. cubensis strains.\n\nThe R173G mutation is also unique to P. cubensis “P.envy” when considering non-cubensis species.\n\nGrey is no alignment, Blue is reference allele, Aqua is low impact variant and Red represent High Impact SNPs as according to SNPeff.\n\ntBLASTn search of P. tampanensis, P. galindoi, P.cubensis and P. azurenscens for PsiK, PsiH, PsiD and PsiM reveals a fragmented psilocybin synthesis cluster with PsiM most often being on large but independent contigs disrupting the contiguity of the psilocybin synthesis cluster.\n\nWe constructed a phylogenetic tree (Figure 7) of the various genomes. Many of the genomes share strain names but were acquired from different spore banks (PS versus SW versus ITW versus Mush). These phylogenetically cluster together as expected. Many samples were sequenced multiple times as biological replicas and are represented in the sample nomenclature as Name_replica_vendor.\n\nPanaeolus Copelandia samples has an P. cubensis ITS sequence is likely a mislabeled sample.\n\n\nConclusions\n\nThese data support both Reynolds et al. and Awan in that psilocybin synthesis appears to have evolved both a conserved ~20 kb cassette seen in many P. cubensis fungi but also a less clustered pathway in regards to a non-contiguous PsiM gene that still needs further characterization and scrutiny. Alternative psilocybin production has also been suggested in the cicada-infecting Massospora spp. fungi (Boyce et al. 2019). Taken together, these data underscore the need for further exploration of psilocybin genomics for alternative or redundant synthesis pathways. Given the divergence of the other psilocybin-producing mushrooms, simply mapping reads from other Psilocybe species to the P. cubensis “P.envy” reference genome can be misleading. Until more complete references exist for the P. tampanensis, P. azurescens and P. galindoi, searching for conserved amino acid sequences more tolerant to synonymous DNA mutations will be required. The genetic variation in the species is substantial and these genomes will help to further correlate genotype to chemotype associations for this nascent field.\n\n\nMethods\n\nSpores were obtained from four vendors (sporeworks.com, Premiumspores.com, Mushrooms.com and InoculateTheWorld.com). Spore preparations utilized a modified DNA isolation procedure described in McKernan et al. (McKernan 2021). Briefly 1.4 mL of spores was centrifuged, decanted and resuspended in 200 μL of ddH2O. 25 μL of a thaumatin-like protein was added and incubated at 37°C (Medicinal Genomics part #420206) for 30 minutes. 12.5 μL of MGC lysis buffer was added and incubated at 65°C for 30 minutes with 9 steel beads. Vortexing was performed every 7 minutes. Lysed sample were micro-centrifuged and 200 μL of supernatant was aspirated and added to 250 μL of Medicinal Genomics (MGC) binding buffer (MGC part# 420001) for magnetic bead isolation. The samples were incubated with the MGC magnetic bead mixture for 10 minutes, magnetically separated and washed two times with 70% ethanol. The beads were dried at 37°C for 5 minutes to remove excess ethanol and eluted with 25 μL of ddH2O\n\nFragmentation\n\nGenomic DNA (gDNA) was quantified with a Qubit (Thermo Fisher Scientific) and normalized to reflect 4–8 ng/μL in 13 μL of TE buffer. Libraries were generated using enzymatic fragmentation with the NEB Ultra II kits (NEB part # E7103). Briefly, 3.5 μL of 5× NEB fragmentation buffer and 1 μL of Ultra II fragmentation enzyme mix are added to 13 μL of DNA. This reaction was tip-mixed 10 times, vortexed, and quickly centrifuged. Fragmentation was performed in a BioRad CFX96 thermocycler at 3.5 minutes at 37°C, 30 minutes at 65°C. The reaction was kept on ice until ready for adaptor ligation.\n\nAdaptor ligation\n\nThe master mix for ligation was prepared on ice using 0.75 μL of Agilent SureSelect Adaptor Oligo Mix, 0.5 μL of ddH2O, 15 μL of New England Biolabs (NEB) Ultra II Ligation Master Mix, 0.5 μL of NEB Ligation enhancer for a total reaction volume of 16.75 μL.\n\nLigation was performed by the addition of 16.75 μL of ligation master mix to the 17.5 μL Fragmentation/End Prep DNA reaction mixture, incubate for 15 minutes at 20°C. To purify excess adaptors and adaptor dimers, vortex at room temp AMPure XP beads (Beckman Coulter #A63881) to resuspend and add 16 μl (approximately 0.45×) of resuspended AMPure XP beads to the ligation reactions. Mix well by pipetting up and down at least 10 times. Incubate the mixture for 5 minutes at 25°C. Put the PCR plate on an appropriate magnetic stand (Medicinal Genomics #420202) to separate beads from supernatant. After the solution is clear (about 5 minutes), carefully remove and discard the supernatant. Be careful not to disturb the beads that contain DNA targets. Wash the magnetic beads by adding 200 μL of 70% ethanol to the PCR plate while in the magnetic stand. Incubate at room temperature for 30 seconds, and then carefully remove and discard the supernatant. Repeat the ethanol wash once for a total of 2 washes. Remove trace amounts of ethanol from the beads. Air dry beads for ~7 minutes while the PCR plate is on the magnetic stand with the lid open. Remove PCR plate from magnet and elute DNA target from beads into 10 μL of H2O, transfer 9 μL cleaned DNA to a fresh well.\n\nPCR amplification\n\nAdd 12.5 μL 2× NEBNext Q5 Hot Start Master Mix (New England Biolabs #M0492S) to 9 μL ligated DNA, then add 3.5 μL NEB 8-bp index primer/universal primer. The reaction was run the cycling program using 98°C for 30 seconds as an initial denaturization step. 6 cycles of denaturization, annealing and extension were performed cycling between 98°C for 10 seconds and 65°C for 75 seconds. A final 65°C for 5 minutes was performed with a final 4°C forever step.\n\nPCR reaction cleanup\n\nResuspend room temp AMPure XP beads with a brief vortex. Add 15 μL of resuspended AMPure XP beads to the PCR reactions (~25 μL). Mix well by pipetting up and down at least 10 times. Incubate mixture for 5 minutes at room temperature. Put the PCR plate on an appropriate magnetic stand to separate beads from supernatant. After the solution is clear (about 5 minutes), carefully remove and discard the supernatant. Be careful not to disturb the beads that contain DNA targets. Add 200 μL of 70% ethanol to the PCR plate while in the magnetic stand. Incubate at room temperature for 30 seconds, and then carefully remove and discard the supernatant. Repeat the ethanol wash once. Air dry beads for 7 minutes while the PCR plate is on the magnetic stand with the lid open. Elute DNA target from beads into 15 μL of nuclease free H2O, transfer 15 μL into a fresh well.\n\nSample quality control and sequencing\n\nLibraries were evaluated on an Agilent Tape Station prior to pooling for Illumina sequencing. Sequencing was performed by GeneWiz, Cambridge MA. A total of 690 million paired reads (2×150 bp) were generated, averaging over 12 million read pairs per sample and a total sequence of 207 Gb.\n\nReads were assembled with MegaHit v.1.2.9 (https://academic.oup.com/bioinformatics/article/31/10/1674/177884) (Li et al. 2015; Li et al. 2016). The Nextflow mapping and assembly pipeline is published on GitHub. Quast 5.0 (http://quast.sourceforge.net) was used to calculate the assembly quality statistics (Gurevich et al. 2013). Sequencing data is deposited in NCBI under Project ID PRJNA700437 and PRJNA687911.\n\nReads were mapped to the P. cubensis “P.envy” reference and to their own assemblies to generate BAM files and coverage statistics using bwa-mem (version 0.7.17-r1188).\n\n\n\nA workflow for this is deposited in github. https://github.com/mclaugsf/mgc-public/blob/master/AOAC_TYM_ERV/bwa-pair.nf\n\n\nVariant analysis\n\nIllumina whole-genome shotgun data (McKernan et al. NCBI Project: PRJNA687911) was mapped to the P. cubensis “P.envy” HiFi reference assembly using bwa-mem (version 0.7.17-r1188), samtools (version 1.8), sorted with sambamba (version 0.6.7) and variants were identified using bcftools (v1.10.2) (Danecek et al. 2021).\n\n\n\nThe VCF files were merged using bcftools and left-aligned to split up multi-allelic entries\n\n\n\nThe annotation from the funannotate pipeline was converted from gff3 format into SnpEff (v4.3t. 2017-11-24) database as described here (https://pcingola.github.io/SnpEff/se_buildingdb/)\n\n\nPhylogenetic analysis\n\nPhylogentic analysis utilized APE (v5.3.) and SNPRelate (v. 1.20.1) (Zheng et al. 2012; Paradis and Schliep 2019).\n\nCoverage analysis was performed using BAM files mapped to the P. cubensis “P.envy” genome reference using bwa-mem as described above (Li 2018). BAM files were analyzed using pileup.sh from the BBmap version 4/30/2020 (http://bib.irb.hr/datoteka/773708.Josip_Maric_diplomski.pdf). The Heatmap was generated using Heatmap.2 from the gplots version 3.1.1 in R Studio (https://www.rdocumentation.org/packages/gplots/versions/3.1.1/topics/heatmap.2).\n\n\nData availability\n\nZenodo: Underlying data for ‘A whole genome atlas of 81 Psilocybe spp. genomes as a resource for psilocybin production’. https://doi.org/10.5281/zenodo.5062843 (McKernan et al. 2021).\n\nThe project contains the following underlying data:\n\nAccession number: NCBI, Project ID PRJNA700437 and PRJNA687911\n\nRoot URL: https://www.ncbi.nlm.nih.gov/search/all/?term=PRJNA700437\n\nAccession number URL: https://www.ncbi.nlm.nih.gov/search/all/?term=PRJNA687911\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAttademo L, Bernardini F: Are dopamine and serotonin involved in COVID-19 pathophysiology? Eur J Psychiatry. 2021; 35: 62–63. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAwan: Convergent evolution of psilocybin biosynthesis by psychedelic mushrooms. BioRXIV. 2018. Publisher Full Text\n\nBogenschutz MP, Podrebarac SK, Duane JH, et al.: Clinical Interpretations of Patient Experience in a Trial of Psilocybin-Assisted Psychotherapy for Alcohol Use Disorder. Front Pharmacol. 2018; 9: 100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBoyce GR, Gluck-Thaler E, Slot JC, et al.: Psychoactive plant- and mushroom-associated alkaloids from two behavior modifying cicada pathogens. Fungal Ecol. 2019; 41: 147–164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCarhart-Harris R, Giribaldi B, Watts R, et al.: Trial of Psilocybin versus Escitalopram for Depression. N Eng J Med. 2021; 384: 1402–1411. Publisher Full Text\n\nCreeden JF, Imami AS, Eby HM, et al.: Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection. Biomed Pharmacother. 2021; 138: 111437. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDanecek P, Bonfield JK, Liddle J, et al.: Twelve years of SAMtools and BCFtools. GigaScience. 2021; 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDavis AK, Barrett FS, May DG, et al.: Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021; 78: 481–489. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDechaumes A, Nekoua MP, Belouzard S, et al.: Fluoxetine Can Inhibit SARS-CoV-2 In Vitro. Microorganisms. 2021; 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFricke J, Blei F, Hoffmeister D: Enzymatic Synthesis of Psilocybin. Angewandte Chemie. 2017; 56: 12352–12355. PubMed Abstract | Publisher Full Text\n\nGriffiths RR, Johnson MW, Carducci MA, et al.: Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016; 30: 1181–1197. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGurevich A, Saveliev V, Vyahhi N, et al.: QUAST: quality assessment tool for genome assemblies. Bioinformatics. 2013; 29: 1072–1075. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHashemi H, Haghdoost AA, Haji-Aghajani M, et al.: A Successful implementation of an idea to a nationally approved plan: Analyzing Iran's National Health Roadmap using the Kingdon model of policymaking. Med J Islam Repub Iran. 2018; 32: 46. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi D, Liu CM, Luo R, et al.: MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics. 2015; 31: 1674–1676. PubMed Abstract | Publisher Full Text\n\nLi D, Luo R, Liu CM, et al.: MEGAHIT v1.0: A fast and scalable metagenome assembler driven by advanced methodologies and community practices. Methods. 2016; 102: 3–11. PubMed Abstract | Publisher Full Text\n\nLi H: Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics. 2018; 34: 3094–3100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcKernan K, Liam TK, Yvonne H, et al.: A whole genome atlas of 81 Psilocybe genomes as a resource for psilocybin production. (1.0). Zenodo. 2021. Publisher Full Text\n\nMcKernan K: Whole genome sequencing of colonies derived from cannabis flowers and the impact of media selection on benchmarking total yeast and mold detection tools. Zenodo. 2021. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParadis E, Schliep K: ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. Bioinformatics. 2019; 35: 526–528. PubMed Abstract | Publisher Full Text\n\nReynolds HT, Vijayakumar V, Gluck-Thaler E, et al.: Horizontal gene cluster transfer increased hallucinogenic mushroom diversity. Evol Lett. 2018; 2: 88–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoss S, Bossis A, Guss J, et al.: Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016; 30: 1165–1180. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchloer S, Brunotte L, Goretzko J, et al.: Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect. 2020; 9: 2245–2255. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchloer S, Brunotte L, Mecate-Zambrano A, et al.: Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol. 2021; 178: 2339–2350. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTullis (2021): How ecstasy and psilocybin are shaking up psychiatry. Nature. 2021; 589, 506–509. PubMed Abstract | Publisher Full Text\n\nZheng X, Levine D, Shen J, et al.: A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics. 2012; 28: 3326–3328. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZimniak M, Kirschner L, Hilpert H, et al.: The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue. Sci Reports. 2021; 11: 5890. Publisher Full Text"
}
|
[
{
"id": "95528",
"date": "19 Oct 2021",
"name": "Bryn T M Dentinger",
"expertise": [
"Reviewer Expertise genomics",
"phylogenetics"
],
"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 present genomic data from 81 samples of putative Psilocybe spp. The source of the samples used for sequencing is problematic in several ways, not the least being clearly documented misidentification and contamination. This reality limits the accuracy of the interpretations made. Moreover, these results are not reproducible without some form of voucher material, but the authors make no mention that such material exists. Therefore, the interpretation of the data presented is entirely dependent on identifications provided by the retail vendors that supplied the spore samples. Yet there is little to suggest that these have the appropriate authority or independently verifiable reference library to justify these identifications.\nUltimately, then, what the authors present are genomic data for 81 spore samples from what are putatively identified as Psilocybe spp., but which most appear to be strains of the widely cultivated P. cubensis. Still, these are only verified by corroborating data from spore supplies sourced from a few vendors. In my opinion, this is not very rigorous science (although I must sympathize with the difficulty presented by legal authorities to do much better). Nonetheless, the genomic data do provide some preliminary insight into the variation of the psilocybin biosynthesis pathway that may be expected from variants of P. cubensis and confirms earlier reports of variation in other Psilocybe spp., including the potential existence of an alternative, non-canonical pathway.\nOverall, the manuscript seems hastily written. The Introduction is brief and framed around what appears to be a misinterpretation of the published literature. There are many misspellings, grammatical errors, and awkwardly worded statements throughout. Capitalizations and italics are not used in a consistently appropriate way. The authors should also provide authorities of scientific names at first use to avoid nomenclatural ambiguity.\nMore specific comments are below:\nThe potential therapeutic value of psilocybin for SARs-CoV-2 seems a bit hand-wavy.\n\n“Two models have been proposed for psilocybin production in Psilocybe spp. Horizontal gene transfer has been thoroughly described by Reynolds et al. and Fricke et al., while convergent evolution has been proposed by Awan (Fricke et al. 2017; Awan 2018; Reynolds et al. 2018).”\nThis is incorrect. None of these studies proposed either HGT nor convergent evolution for psilocybin biosynthesis IN Psilocybe spp. HGT has been proposed as the mechanism for the gain of psilocybin biosynthesis in other genera (e.g., Panaeolus, Pluteus) and convergent evolution has been proposed for the gain of psilocybin biosynthesis in the genus Inocybe. Thus, these statements are inaccurate representations of the published literature and need to be corrected.\n\n“Given the broad geographic distribution of psilocybin-producing mushrooms and the history of human cultivation and selection for psilocybin-producing strains, these models may not be mutually exclusive. “\nI agree that these models are not necessarily mutually exclusive (indeed, none of the previous studies suggested so), but what does the “history of human cultivation and selection for psilocybin-producing strains” have to do with it? Moreover, can the authors cite the statement of “history of human cultivation” (what history)? And what evidence is there for “selection for psilocybin-producing strains”?\n\n“These non-conical psilocybin-synthesizing genomes…”\nDo the authors mean “non-canonical”? N.B. the term “conical” appears throughout the manuscript where I suspect the term “canonical” is intended.\n\n“…99%, 100%, and 91% ITS sequence identity to a Psilocybe tampanensis sequence described by Rockefeller et al. (NCBI accession number: MH220315.1)”\nFirst, “described” is not the correct term. Second, the sequence in GenBank was derived from a specimen identified as P. tampanensis. Third, the percent identities cited are not sufficient --- percent identity over what portion of the sequence? And was this one sequence the top hit for all three of the ITS sequences derived from the WGS?\n\nThe degree to which the spore samples apparently consisted of contaminants and in at least one clear case a gross misidentification calls into question the identity, reliability and reproducibility of the results from the other “strains.”\n\n“Contaminated libraries are usually detectable with bimodal sequencing coverage as its rare for the organisms to be equimolar. All five non-P. cubensis species have very uniform sequence coverage across the contigs and high BUSCO completion scores with strong ITS sequence implying clean assemblies.”\nThis is one way to determine endogenous content, but other methods to detect contaminant DNAs in metagenomic datasets (e.g., taxon-annotated GC plots) should be explored to corroborate the indirect inference from sequencing coverage (esp. b/c this assumes that target and contaminant sequencing coverage is bimodal, which is not necessarily the case if there are multiple contaminants and/or contaminants are at varying proportions relative to target).\n\n“In combination, these data demonstrate close relatedness of Psilocybe tampanensis and Psilocybe galindoi but distant relatedness to the Psilocybe cubensis “P.envy” reference genome. “\nThe authors should be more cautious about this interpretation, as there is no evidence to support the identifications of the strains supplied nor their identity with authentic specimens (e.g., types or others). Who knows if these spores labeled as these species/strains are correct?\n\n“Given the known psilocybin production in these alternative Psilocybe species, these data also imply an alternative synthesis pathway must exist in these species as suggested by Awan.”\nIt should be made clear that in Awan et al., it was proposed that convergent evolution explains psilocybin biosynthesis in Inocybe, a distant relative of Psilocybe. On the other hand, Awan et al. did suggest there may be an alternative pathway present in the Psilocybe genomes. Which of these are the authors referring to here?\n\n“PsiK exists in the conical cluster on scaffold_7 but also has a close homolog on scaffold_1.”\nWhile this may be true, the high potential for contaminant DNAs in the samples sequenced suggests this may be the result of a metagenome assembly. This alternative needs to be ruled out.\n\n“biological replicas”\nReplicates? And what evidence is there that these are truly biological replicates rather than the same spores being sourced from multiple places? (what’s the likelihood that these companies are all deriving their spores independently?)\n\n“These data support both Reynolds et al. and Awan in that psilocybin synthesis appears to have evolved both a conserved ~20 kb cassette seen in many P. cubensis fungi but also a less clustered pathway in regards to a non-contiguous PsiM gene that still needs further characterization.”\nPlease be more specific wrt what in these previous studies is being cited. At the beginning the authors incorrectly cite these papers as evidence of HGT and convergent evolution of psilocybin biosynthesis in Psilocybe. So what exactly is being cited here?\n\n“Given the divergence of the other psilocybin-producing mushrooms, simply mapping reads from other Psilocybe species to the P. cubensis “P.envy” reference genome can be misleading.”\nWhy did the authors not bother to attempt to align these to the other existing Psilocybe genomes? Two other (potentially closely related) genomes are available (P. cyanescens and P. serbica), yet the authors made no attempt to align their reads from the putative P. tampanensis, P. galindoi, or P. azurescens to them (the latter is a potential synonym of P. cyanescens). This could help further clarify the source of the low mapping rates to \"P. envy\" and may provide further insight into the non-canonical homologs of PsiK and PsiM that they report here.\n\nMethods: generally thorough enough to be reproducible, but in some parts it reads like a laboratory protocol rather than text written for a manuscript.\n\nCan the authors display the phylogenetic tree differently? As it currently is, it is difficult to interpret clustering because the branch lengths have been transformed in a way that is awkward to read. I would also suggest using an unrooted tree and provide branch support values.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7559",
"date": "17 Dec 2021",
"name": "Kevin McKernan",
"role": "Author Response",
"response": "Version 2 Per recommendation of the Moderator/Editor. Response to Dentinger and Bradshaw We appreciate the many helpful comments from Dentinger and Bradshaw. Many of them are on point and the manuscript will be adjusted accordingly. A few comments appear to be a non-addressable given the legal status of live tissue of Psilocybe cubensis. As the reviewers themselves point out, this is not unique to this manuscript. We will address these points as well as we can, given the current legal climate. 1) The potential therapeutic value of psilocybin for SARs-CoV-2 seems a bit hand-wavy. Fair point. The SARs connections have since strengthened and could in fact use more detail and citations to support. The 9K person clinical trial for Fluvoxamine just completed this month and is showing better efficacy than the vaccines. We have added more references and language to back this association and we have itemized the link as being associative to address the reviewers concerns over this nascent field. 2) This is incorrect. None of these studies proposed either HGT nor convergent evolution for psilocybin biosynthesis IN Psilocybe spp. HGT has been proposed as the mechanism for the gain of psilocybin biosynthesis in other genera (e.g., Panaeolus, Pluteus) and convergent evolution has been proposed for the gain of psilocybin biosynthesis in the genus Inocybe. Thus, these statements are inaccurate representations of the published literature and need to be corrected. This has been corrected. This is an important and valid critique. A prior draft of this manuscript referred to this as ”hallucinogenic mushrooms”. In attempting to be more specific, we erroneously replaced this with Psilocybe spp. Which is too narrow and excludes the relevant families raised by the reviewers. 3) “Given the broad geographic distribution of psilocybin-producing mushrooms and the history of human cultivation and selection for psilocybin-producing strains, these models may not be mutually exclusive. “ We have removed the discussion of human selection. 4) Do the authors mean “non-canonical”? N.B. the term “conical” appears throughout the manuscript where I suspect the term “canonical” is intended. We have changed the conical/canonical language to “gene cluster” as this appears to be the more agreed upon language describing this recently described region of interest. 5) First, “described” is not the correct term. Second, the sequence in GenBank was derived from a specimen identified as P. tampanensis. Third, the percent identities cited are not sufficient --- percent identity over what portion of the sequence? And was this one sequence the top hit for all three of the ITS sequences derived from the WGS? We have changed this to “reported to NCBI by”. We agree and clearly state the Rockefeller sequence is from P.tampanensis as you suggest. The listed percentages are across the full-length accession described by Rockefeller (946bp). We have annotated the length of the alignments and included an additional accession from Wesselink et al. from P.mexicana. 6) The degree to which the spore samples apparently consisted of contaminants and in at least one clear case a gross misidentification calls into question the identity, reliability and reproducibility of the results from the other “strains.” We believe this is an unfair critique as our transparency is being weaponized against us. We could have easily omitted the contaminated sample from the manuscript but believe negative results are informative. It is important for readers to know that contamination does exist in the circulating spore preps and it is important to build tools to detect and screen for them. We should also be careful not to blame the spore providers for this contamination given endofungal bacteria are known to exist in many fungi and we can’t be certain of the source of the contamination (Aspergillus is ubiquitous and our lab handles it). To attack the other sample veracity, because the authors were honest about one obvious contamination event out of 81 genomes is counter-productive and leads to more scientists hiding their negative results to avoid critiques like this. 7) This is one way to determine endogenous content, but other methods to detect contaminant DNAs in metagenomic datasets (e.g., taxon-annotated GC plots) should be explored to corroborate the indirect inference from sequencing coverage (esp. b/c this assumes that target and contaminant sequencing coverage is bimodal, which is not necessarily the case if there are multiple contaminants and/or contaminants are at varying proportions relative to target). We provided read mapping rates for all libraries. Highly contaminated samples don’t produce 90% read mapping rates unless the contamination is of the same species. This is evident in the assembly statistics we provided for every genome sequenced. Furthermore, assemblies are filtered with tBLASTn to evaluate genes with high amino acid sequence homology to P.cubensis specific genes (PsiK,PsiM,PsiD etc). Any additional minor contamination is thus filtered from this part of the analysis. Nevertheless, we have added the suggested Taxon-annotated GC plots for the 5 of the P.cubensis libraries and 5 of the non-cubensis libraries per the reviewers recommendations (supplementary figure 1-4). There is some bacterial contamination evident in the P.galindoi sample but as mentioned before, we have filtered the contigs of interest out using tBLASTn for the relevant genes of interest. This isn’t a relevant critique related to the assessment of the contiguity of the Psilocybin gene cluster in question. 8) The authors should be more cautious about this interpretation, as there is no evidence to support the identifications of the strains supplied nor their identity with authentic specimens (e.g., types or others). Who knows if these spores labeled as these species/strains are correct? We have added additional disclaimers to address the concerns raised over the spore providers veracity. In many ways these 81 genomes best address the very concerns these reviewers present. We were careful to sequence many strains with identical names from multiple vendors so this question could be addressed. There is no other biobank of P.cubensis that has this level of public sequence verification on the nomenclature system. We’d like to emphasize to the editors and readership that the reviewers correctly point out that the psilocybin legality issue plagues all studies in P.cubensis but this should not be used as a club to discredit manuscripts generating data that might address the very issue. It can even be seen in the reviewers own excellent work which we cite. Below is the methods section from Awan et al. \"Psilocybe cyanescens genome Illumina sequencing DNA was extracted from fresh whole mushrooms of P. cyanescens by first freezing with liquid nitrogen and then grinding the tissue into a fine powder with a mortar and pestle in 2X CTAB buffer following a modified protocol from Doyle (1991) DNA extracts were then cleaned through a CsCl density-gradient centrifugation and resuspended in TE buffer. DNAs were sent to Eurofins Scientific (Ebersberg, Germany) for 2 x 150 paired-end sequencing on an Illumina HiSeq 2500 platform.\" No information is provided on how to acquire the samples Awan et al. sequenced. We have at least provided a vendor name and we were careful to collect samples with the same name from multiple vendors in replicates to test the veracity of the spore providers nomenclature. We believe our manuscript does a more thorough job to address such concerns than manuscripts prior as most previous studies simply sequence a few samples without replicates or guidance on spore providers. While this is not the core focus of our manuscript, we would turn the reviewer’s attention to the sequence and the SNP metrics provided for the samples with the same name but from multiple different spore providers as these metrics are informative to this question. This is better sample veracity than we observe in the cannabis market and we are unaware of any study that has this level of sequence data to authenticate the nomenclature system in Psilocybe. We will reiterate that the nomenclature in the field is still very nascent and unvalidated. Sequencing studies like this are the first steps required to catalog it. 9) It should be made clear that in Awan et al., it was proposed that convergent evolution explains psilocybin biosynthesis in Inocybe, a distant relative of Psilocybe. On the other hand, Awan et al. did suggest there may be an alternative pathway present in the Psilocybe genomes. Which of these are the authors referring to here? We have clarified Awan et al. description of convergent evolution. 10) “PsiK exists in the conical cluster on scaffold_7 but also has a close homolog on scaffold_1.” While this may be true, the high potential for contaminant DNAs in the samples sequenced suggests this may be the result of a metagenome assembly. This alternative needs to be ruled out. We believe this is a misunderstanding. Scaffold_1 is from a peer reviewed Pacific Biosciences P.envy HiFi assembly. This genome is an annotation grade, 32 contig assembly with a N50 over 3.3Mb. We have labelled each scaffold in that paragraph with P.envy scaffold # to help clarify which references we are referring to. P.envy has been annotated and is in NCBI. NCBI filters for such contaminant when importing reference grade genome assemblies and rarely to do bacterial contaminants consist of a 4.5Mb HiFi chromosome (with a telomere) that shares equal coverage to all of the other Psilocybe contigs. Scaffold_1 and Scaffold_7 in the P.envy reference genome have already been screened for contaminants (source). 11) Replicates? And what evidence is there that these are truly biological replicates rather than the same spores being sourced from multiple places? (what’s the likelihood that these companies are all deriving their spores independently?) Biological replicates from the same vendor are critical to understand how much the sequencing process varies on the same biological sample. The study was careful to select inter-vendor and intra-vendor replicates. This question is best addressed with the data now public with this manuscript. Of note is the very high genotyping concordance between samples with the same name from the same vendor (Malabar). This genotyping concordance is shared with Malabar samples from different vendors (SW and PS). Contrary to this, B-plus samples from different vendors have lower genotyping concordance. This suggests the spore providers are not clones of each other but do have some strains that appear to be clonal with other providers while also hosting some unique genetics under the same name. This data is in Figure 1. A complete genomic audit trail on the vendor veracity is outside the scope of this preliminary analysis but data does currently exist in Figure 1 to address these concerns. All of the FastQ files are in the SRA for people to explore these other questions. 12) Please be more specific wrt what in these previous studies is being cited. At the beginning the authors incorrectly cite these papers as evidence of HGT and convergent evolution of psilocybin biosynthesis in Psilocybe. So what exactly is being cited here? We have clarified the Family/Genus regarding Reynolds and Awan. 13) Why did the authors not bother to attempt to align these to the other existing Psilocybegenomes? Two other (potentially closely related) genomes are available (P. cyanescensand P. serbica), yet the authors made no attempt to align their reads from the putative P. tampanensis, P. galindoi, or P. azurescens to them (the latter is a potential synonym of P. cyanescens). This could help further clarify the source of the low mapping rates to \"P. envy\" and may provide further insight into the non-canonical homologs of PsiK and PsiM that they report here. We have already compared the P.envy references to these submissions in McKernan et al.(link). We will reiterate that the gene cluster is intact in those species. Neither of these suggested references (P.serbica and P.cyanescens) have raw reads in the SRA. As a result, they cannot be run through blobtools for Taxon-annotated GC plots (coverage required from a mapped BAM file) to address the contamination problems on the same footing as the other data you are asking for comparisons to. Nevertheless we have mapped the reads from 5 non-cubensis strains to the above references and added a new table to demonstrate these results (Table 1). We also included 3 cubensis strains as a comparison. You can see from this work that P.azurescens is indeed more closely related to P.cyanascens, as the reviewers suggest, but P.tampanensis and P.galindoi are more closely related to each other but more distant to P.cyanescens. 14) Methods: generally thorough enough to be reproducible, but in some parts it reads like a laboratory protocol rather than text written for a manuscript. We have reformatted this section to read more as a journal method than a lab protocol. 15) Can the authors display the phylogenetic tree differently? As it currently is, it is difficult to interpret clustering because the branch lengths have been transformed in a way that is awkward to read. I would also suggest using an unrooted tree and provide branch support values. We have added a link to the newick file so readers can redisplay the phylogenetic tree multiple different ways. We’d like to thank the reviewers for their careful review of the manuscript and for pointing out critical taxonomy considerations."
}
]
}
] | 1
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https://f1000research.com/articles/10-961
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https://f1000research.com/articles/10-1076/v1
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25 Oct 21
|
{
"type": "Brief Report",
"title": "Weak and strong ties and its connection to experts' problem-solving styles in scaffolding students' PBL activities on social media",
"authors": [
"Aznur Hajar Abdullah",
"Tse Kian Neo",
"Jing Hong Low",
"Tse Kian Neo",
"Jing Hong Low"
],
"abstract": "Background: Studies have acknowledged that social media enables students to connect with and learn from experts from different ties available in the students’ personal learning environment (PLE). The inclusion of experts in formal learning activities through social media such as in scaffolding problem-solving activities helps students see the practicality of experts’ thinking in solving real-world problems. However, studies that evaluate experts’ problem-solving styles and how these influence the experts' thinking process in delivering the know-how to students on social media based on the ties that the students have with the experts in social media are scarce in the extant literature. The study aimed to explore the problem-solving styles that the experts portrayed on Facebook based on their ties with the students. Methods: This study employed a simultaneous within-subject experimental design which was conducted in three closed Facebook groups with 12 final year management students, six business experts, and one instructor as the participants. The experts were invited by the students from the weak and strong ties in their PLE. Hinging on the Theory of Fluid and Crystallised intelligence and the Strength of Weak Ties Theory, this study employed thematic analysis using the ATLAS.ti qualitative data analysis software to map the experts’ comments on Facebook. Results: The use of strong ties in combination with weak ties balances out the negative aspects of the business experts’ problem-solving styles. All the experts used both fluid and crystallised intelligence in scaffolding the students’ learning; however, the degree of its usage correlated with the working experience of the experts. Conclusion: The use of weak or strong ties benefited the students as it expedited their problem-solving tasks since the experts have unique expertise to offer depending on the degree of their working experiences and the proximity of the students’ relationship with the experts.",
"keywords": [
"Problem-based learning",
"Facebook",
"business experts",
"problem-solving styles"
],
"content": "Introduction\n\nPersonal learning environment (PLE) is a self-driven learning space that allows individuals to collaborate, connect and participate using one or more technological artifacts, platforms, or online tools available in the personal learning space.1 Siemen,2 the founder of social connectivism theory, asserted that the inclusion of PLE is vital in online learning as students could form connections with external sources of more experienced people from dispersed geographical locations that could contribute knowledge and experiences that essentially aid students’ educational experience.3\n\nThe use of social media embedded in students’ PLE enables students to gain access to experts who could support their formal and informal learning.4,5 Social media allows students to tap into the connections of the weak ties from which they might draw resources.6 In his famous strength of weak ties’ experiment, Granovetter7 reported that people secure jobs mostly through weak ties by getting job information from acquaintances rather than close friends or family. Weak ties are defined by relationships that involve infrequent contact such as distant relatives, acquaintances, or people unknown to us. Meanwhile, strong ties refer to relationships of people who are closely in touch such as family members and close friends. Granovetter argued that although weak ties display low intimacy and emotional intensity than strong ties, it offers vital benefits such as providing more social support and networking strength.8 It is reasonable to postulate that students could utilise their strong and weak ties by engaging with experts in their PLE on social media to support learning. Unfortunately, existing studies have not ascertained this assumption.\n\nRecently, the use of experts to facilitate students’ learning in online settings has gained substantial attention among problem-based learning (PBL) scholars, mainly because expert thinking differs vastly from novice thinking.9 Horn and Cattel‘s10 Theory of Fluid and Crystallized Intelligence described experts as having more crystallised intelligence embedded than novices when dealing in knowledge-rich problem situations where the goals of a problem are uncertain and the solutions are not straightforward.10–12\n\nTherefore, experts devise solutions faster than novices because they use necessary knowledge based on their life experiences that are stored in long-term memory which makes up their crystallised intelligence. Additionally, experts also demonstrate fluid intelligence, namely the ability to reason and adapt without the need for substantial levels of prior learning when confronted with new problems or situations. This enables business experts, for instance, to accustom themselves to an ever-changing contemporary business environment characterised by volatility, uncertainty, fuzziness, and complexity.13\n\nIn contrast, novices tend to lose direction when dealing with complex problem-solving, especially when confronting information that is presented simultaneously in an online context. Consequently, when placed in online platforms to solve complex problems, students often need a more experienced individual to guide their thinking to approximate the experts’ reasoning14 and to reconcile the misunderstanding. The use of PBL in technology-rich environments such as social media allows students to receive online scaffolding, a form of assistance from more experienced people who could guide them in performing unfamiliar tasks they are incapable of performing on their own in online mediated platforms.4 Students may integrate their PLE with unlimited arrays of scaffolders who are socially connected in social media including instructors, peers and experts to assist in the problem-solving tasks.\n\nSeveral studies have investigated how experts deal with novices in problem-solving activities.15–17 Nevertheless, very few have explored the patterns of experts’ problem-solving styles that are drawn via the use of strong and weak ties to support problem-solving activities with students.\n\nObjectives and rationales\n\nThis study explored the patterns of experts’ problem-solving styles and intelligence characteristics when reasoning with students in problem-solving activities whereby the patterns were mapped against the ties the students established in their PLE. Since experts think differently from novices, understanding these patterns would help novices and educators gain insight into the scaffolding provided by experts.\n\n\nMethods\n\nThe sampling techniques and the instruments used were reported according to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline,18 a popular guideline in social science research.\n\nThis study was approved by the Research Ethical Committee of Multimedia University (EA2012021). Initially, all participants were briefed on the assignment deadlines and expected roles in the problem-solving protocols. Subsequently, written informed consent for participation and publication of the research has been obtained from the participants. All communications on Facebook were transcribed and their identities were concealed for maintaining the participants’ anonymity following STROBE guideline and Subirats et al.19\n\nStudy design, setting and participants\n\nThe researchers made a call for volunteers who were undertaking a global management course at a Malaysian private university to participate in solving a decision-making business problem. The volunteers were required to invite along two business experts from their PLE to scaffolded them for eight weeks. The requirements of the business experts were set as follows: having substantial working experience of 10 years or more, hold a managerial position and the experts must have one of the following ties with the students; both experts are from strong, weak or both ties. Finally, 12 final-year baccalaureate students who met the research criteria volunteered to participate. This study used a simultaneous within-subject experimental design for three groups comprising four students each (two from Cohort 2017 and one from Cohort 2018) were assigned in a closed group Facebook to communicate, clarify issues, and share resources. Furthermore, this group arrangement is common in PBL studies.20 Facebook was selected because of its effectiveness in supporting various degrees of ties and capability to accommodate small PBL groups.21 The Facebook communications were transcribed and available in a dataset.22 Students were scaffolded by the experts and instructor following Ge and Land’s23 problem-solving protocol which involved problem identification, developing and evaluating solutions, and assessing alternative solutions.\n\nThe students documented their work on Google documents that could be assessed only by the instructor, experts and students for each respective group.\n\nTable 1 depicts the business experts’ profiles. Groups 1 and 2 used weak ties. A student in Group 1 invited two experts from her former internship company during her diploma studies. Group 2 invited two experts whom the students searched from an organisation’s website; none of the students knew the experts before inviting them to participate in this study. Group 3 used a combination of weak and strong ties. The strong tie was one of the students’ close relatives while the weak tie was one of the student’s internship acquaintances. The business experts from Groups 1 and 3 have 20 to 30 years of work experience in the shipping and airport management industry, respectively. Meanwhile, the experts in Group 2 have 10-15 years of work experience in the e-commerce industry.\n\nMethods of analysis\n\nFriese et al.24 recommended the use of deductive thematic analysis when a pre-existing framework is available. Therefore, the discussions between the business experts and the students were thematically mapped using Selby's25 three problem-solving styles. These included problem-solving preferences (explorer vs. developer) which were coded as M: Explorer and M: Developer; the manner of processing (internal vs. external) coded as MP: Internal and MP: External; and finally, ways of deciding (people vs task preference) coded as WOD: People and WOD: Task. The Theory of Fluid and Crystallised Intelligence10 was used to map the type of intelligence the experts primarily demonstrated. ATLAS.ti software (Version 8.4.25.0) was used to analyse the identified themes to reflect the business experts’ responses. Acknowledging that there is available open-source software as alternatives to ATLAS.ti such as QualCoder and Tagguete, many qualitative scholarly papers adopted ATLAS.ti for its user-friendliness for coding and displaying network analysis results. Besides that, ATLAS.ti has a variety of tools to analyse unstructured data.26 Moreover, one of the researchers in this study is well-versed in using ATLAS.ti. For those reasons, ATLAS.ti was chosen.\n\n\nResults\n\nFigure 1 displays the network analysis based on the themes extracted from Facebook discussions. The weak tie experts in Group 1 (Figure 2) displayed a more accommodating approach and a sense of belongingness by using phrases such as “dear team” and “keep moving team”. Selby25 described this as the people preference style where this approach is seen as an effort to maintain harmony in the group. The experts respected the students' own pace of processing information as they required time to digest and internalise the meaning of the information presented to them by the students before responding. In contrast, the business experts from Group 2 (weak ties 2) adjusted their reasoning based on the information the students presented to them first. This sort of arrangement falls under the explorer style. The experts preferred the students exploring all possible options and presenting the latest information before guiding the students based on the materials presented (Figure 3).\n\nLastly, Group 3 which used a combination of both weak and strong ties (Figure 4) showed mixed findings. The strong tie expert (Expert 1 from strong tie) was sensitive to the participants’ feelings and ended her comments with remarks such as “Otherwise, good job all”. This style is categorised as the people preference. The strong tie expert also demonstrated more persistence and patience in scaffolding the students by presenting the developer style. She directed the students beginning with a basic idea and gradually developed the ideas as the students were progressing by making statements such as “I think it would be a good idea if … .”. This characteristic is similar to the style of experts in Group 1. In contrast, the weak tie expert (Industry Expert 2) exhibited a task preference style where the tone of the discussion was more of task accomplishment tend to be free from emotion and are focused on the tasks, which sometimes resemble the explorer style25 as the experts were inclined to share only after receiving information from the students.\n\nThese sorts of problem-solving styles of the experts correlated with the types of intelligence used and working experiences. Experts from Group 2 (with 10-15 years of work experience) exhibited more fluid intelligence as they were flexible in dealing with new information in thinking and reasoning with the students. In contrast, the business experts in Groups 1 and 3 (with more than 30 years of work experience) demonstrated crystallised intelligence and shared validated business solutions by occasionally sharing how the presented information was linked to their past experiences. The explanations given by the experts in Groups 1 and 3 were also seen as more insightful compared to the guidance provided by experts in Group 2.\n\n\nDiscussion and conclusion\n\nAccording to Bilalic and Gobet,17 the greater the degree of expertise, the more flexible the experts are in responding to new information. The profile of the business experts from Groups 1 and 3 showed they have vast experiential knowledge, rendering them capable of deciphering information from different perspectives. The experts used more technical terms and jargons which necessitated the students to ask a second party to provide the meaning-making for them. Occasionally, the students were observed needing to rely on the other expert or instructor for the meaning-making process (to put the meaning in a context understandable to the students). This is supported by Ryberg20 who claimed that placing students in different degrees of ties sometimes require different participants like the instructor to provide the interpretation of meaning.\n\nDaniel Kahneman,27 in his book “Thinking Fast and Slow”, outlined two thinking systems called System 1 and System 2. System 1 is fast and energy-efficient because it follows the “rule of thumb” and does not involve processing of details; as a result, System 1 thinking is full of shortcomings and biases. In contrast, in System 2, information processing is intricate, time-consuming, and expends more energy, especially when dealing with ill-structured problems. This is where the roles of experts could help in expediting students’ effort by simplifying the need to understand. For novice learners, using System 2 may require a longer time for information processing. Nonetheless, the availability of experts with more work experiences could shorten students’ thinking process because of the experiential knowledge the experts have that resembles their crystallised intelligence. This is consistent with previous studies that confirmed people tend to use more crystallised intelligence as they increase in age.10\n\nAdditionally, the business experts who used more fluid intelligence had different reasoning styles with the students. Instead of offering the information asked by the students straightaway, the experts from Group 2 often asked the students to search for the materials first, and later worked on the materials together with the students. This was possibly done to avoid offering inaccurate advice as a result of using System 1 thinking. The experts needed to verify the information before formulating relevant strategies to scaffold the students. The experts from Group 2 mostly provided policy papers rather than offering specific real-life business evidence that the students could use as a reference. Possibly, the experts expected the students to put in the effort to search for the information first.\n\nThis study also verified that scholars should not equate all weak tie experts as sharing similar problem-solving styles. It is postulated that how the students knew the business experts matters. The business experts from Groups 1 and 3 were from the weak ties; however, the past working relationship that one of the students in each group had with the experts during internship placement led the business experts to display a more empathic attitude towards the students’ learning needs. In contrast, the business experts from Group 2 had no prior relationship with the students, thus their preference for using more task-oriented problem-solving styles. Nonetheless, despite their different styles, the inclusion of the experts in the discussion still accelerated the students' learning, in tandem with previous studies that acknowledged business experts’ inclusion in PBL enhances students’ learning experience.28,29\n\n\nConclusion\n\nThis study contributes towards our understanding of the roles of problem-solving styles and the strength of ties in problem-solving activities on Facebook. The use of networked learning in PBL depends on individualised networking and social collaboration that encourage content generation in problem-solving.21 It can be concluded from the findings that not all experts from the weak ties have similar problem-solving styles. Factors such as the experts’ work experience and how the weak ties were developed played a major role in determining the experts’ problem-solving styles, which indirectly influenced their thinking and reasoning strategies with the students.\n\nThe experts, regardless of whether they were from weak or strong ties, still benefited the students in expediting their problem-solving tasks. Thus, inviting business experts to participate in formal learning on social media by utilising the strong and weak ties the students have should be encouraged as each expert has unique expertise to offer, especially in helping the students see the different sides of complex information that are essential to prepare them for future professional career.\n\nThe use of non-probability sampling involving two experts in each of the three groups in one degree-level management course limits the generalisability of the findings to other courses. Hence, the study’s findings should be evaluated with caution and may only be applied to similar studies, for example, those that examine Facebook use for PBL in management courses.\n\n\nData availability\n\nFigshare: Facebook Discussions captured in ATLAS.ti, https://doi.org/10.6084/m9.figshare.16811542.\n\nThis project contains the following underlying data:\n\nDatafile 1: Transcribed conversation of Group 1\n\nDatafile 2: Transcribed conversation of Group 2\n\nDatafile 3: Transcribed conversation of Group 3\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors would like to extend their gratitude to the participants who took part in this study. The authors would also would like to thank Multimedia University, Malaysia for providing publication sponsorship of this manuscript.\n\n\nReferences\n\nSiemens G: Connectivism: A learning theory for the digital age. elearnspace. 2004.\n\nDabbagh N, Castaneda L: The PLE as a framework for developing agency in lifelong learning. Educ. Technol. Res. Dev. 2020 Dec; 68(6): 3041–3055. Publisher Full Text\n\nSalter MB: Crowdsourcing: Student-driven learning using Web 2.0 technologies in an introduction to globalization. J. Polit. Sci. Educ. 2013 Jul 1; 9(3): 362–365. Publisher Full Text\n\nRyberg T: PBL and networked learning: Potentials and challenges in the age of mass collaboration and personalization. The Wiley Handbook of Problem-Based Learning. 2019 Apr; 3: 593–615. Publisher Full Text\n\nKim C: Out-of-class communication and personal learning environments via social media: Students' perceptions and implications for faculty social media use. Teaching Journalism & Mass Communication. 2017; 7(1): 62.\n\nEllison NB, Vitak J, Gray R, et al.: Cultivating social resources on social network sites: Facebook relationship maintenance behaviors and their role in social capital processes. J. Comput.-Mediat. Commun. 2014 Jul 1; 19(4): 855–870. Publisher Full Text\n\nGranovetter MS: The strength of weak ties. Am. J. Sociol. 1973 May 1; 78(6): 1360–1380. Publisher Full Text\n\nKarsai M, Perra N, Vespignani A: Time varying networks and the weakness of strong ties. Sci. Rep. 2014 Feb 10; 4(1): 1–7. Publisher Full Text\n\nGüss CD, Devore Edelstein H, Badibanga A, et al.: Comparing business experts and novices in complex problem solving. J. Intelligence. 2017 Jun; 5(2): 20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHorn JL, Cattell RB: Refinement and test of the theory of fluid and crystallized general intelligences. J. Educ. Psychol. 1966 Oct; 57(5): 253–270. PubMed Abstract | Publisher Full Text\n\nTawfik AA, Law V, Ge X, et al.: The effect of sustained vs. faded scaffolding on students’ argumentation in ill-structured problem solving. Comput. Hum. Behav. 2018 Oct 1; 87: 436–449. Publisher Full Text\n\nHung W: The 9-step problem design process for problem-based learning: Application of the 3C3R model. Educ. Res. Rev. 2009 Jan 1; 4(2): 118–141. Publisher Full Text\n\nBarlach L, Plonski GA: The Einstellung effect, mental rigidity and decision-making in startup accelerators. Innovation & Management Review. 2021 March.\n\nReilly CM, Kang SY, Grotzer TA, et al.: Pedagogical moves and student thinking in technology-mediated medical problem-based learning: Supporting novice-expert shift. Br. J. Educ. Technol. 2019 Sep; 50(5): 2234–2250. 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PubMed Abstract | Publisher Full Text\n\nSubirats L, Reguera N, Bañón AM, et al.: Mining Facebook data of people with rare diseases: a content-based and temporal analysis. Int. J. Environ. Res. Public Health. 2018 Sep; 15(9): 1877. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIoannou A, Vasiliou C, Zaphiris P: Problem-based learning in multimodal learning environments: Learners’ technology adoption experiences. J. Educ. Comput. Res. 2016 Dec; 54(7): 1022–1040. Publisher Full Text\n\nRyberg T, Larsen MC: Networked identities: understanding relationships between strong and weak ties in networked environments. J. Comput. Assist. Learn. 2008 Apr; 24(2): 103–115. Publisher Full Text\n\nAbdullah N:Low: Facebook Discussions captured in ATLAS.ti. Figshare. 2021. Publisher Full Text\n\nGe X, Land SM: Scaffolding students’ problem-solving processes in an ill-structured task using question prompts and peer interactions. Educ. Technol. Res. Dev. 2003 Mar; 51(1): 21–38. Publisher Full Text\n\nFriese S, Soratto J, Pires D: Carrying out a computer-aided thematic content analysis with ATLAS. ti. MMG Working Paper 18-02. 2018.Reference Source\n\nSelby EC, Treffinger DJ, Isaksen SG, et al.: Defining and assessing problem-solving style: Design and development of a new tool. J. Creat. Behav. 2004 Dec; 38(4): 221–243. Publisher Full Text\n\nSmit B: Introduction to ATLAS. ti for Mixed Analysis. The Routledge Reviewer’s Guide to Mixed Methods Analysis.2021 Jul 12; 331.\n\nKahneman D: Thinking, Fast and Slow. Farrar, Straus and Giroux;2011.\n\nMoallem M, Hung W, Dabbagh N: The Wiley handbook of problem-based learning. Hoboken, New Jersey:Wiley Blackwell;2019 Jan 30. Publisher Full Text\n\nHuang R, Spector JM, Yang J: Educational technology: a primer for the 21st century. Springer;2019 Feb 27. Publisher Full Text"
}
|
[
{
"id": "97804",
"date": "02 Nov 2021",
"name": "Els Boshuizen",
"expertise": [
"Reviewer Expertise Expertise development",
"expert vs novice knowledge and knowledge structure",
"expert vs novice reasoning."
],
"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 investigates how external experts (that is, not connected to the university) with weak or strong ties to the students can support them through social media in their problem-based learning activities.\nIt is investigated in three PBL groups of four students each, who worked on divergent topics, and who invited two domain experts per group. The Facebook platform was used for communication and cooperation as it provides ample opportunities for data collection.\nA couple of theoretical foci were applied: strong vs weak ties; PLE as a means to receive on-line scaffolding; expertise seen as fluid vs crystallised intelligence; aspects of expert-novice interaction; Selby's problem solving styles; system1 vs system2 thinking. One could say that this is an innovative combination of theoretical approaches, however - in my view - it blurs the real innovation in this study, that is, the participation of outsider-experts in student support through many different expert actions: providing information and information sources, pointing out gaps, asking questions, etc. combined (or not) with motivating actions. Also the role of the instructor as a go-between students and experts is an interesting addition. And I agree with the authors that the participation of these experts was successful.\nHaving said that I list a couple of issues that need clarification:\nThe authors should make clear why they introduced the theory of fluid and crystallised intelligence to describe expert reasoning and knowledge use in combination with interaction with novices. Using this theory introduces connotations that might not be intended. Especially in a short article like the present one, it is better to be sparsimonious with concepts used. Very much research has been done on the issue expert-novice communication in PBL including the question whether intermediates might fulfil a better role (for instance by Schmidt and Moust) that does not use these concepts.\n\nFurthermore, the authors should better document how the use of fluid vs crystallise intelligence was coded. And in the Results section it is good practice to provide proof using quotes. The excerpts given provide interesting reading material but they do not show how the researchers coded this.\n\nThe issue of strong vs weak ties is very interesting. I wonder whether the way expert invitation was carried out was sensitive to tie strength. I assume that available expertise was the decisive factor, not kind of tie. It is, of course, interesting whether kind of tie affects communication.\n\nThe issues raised by Bilalic et al. and by Kahneman resonate in different ways with fluid and crystallised intelligence. They are very interesting but by introducing these authors it is more difficult to bring the message across.\n\nSmall issue p7: According to Bilalic, McLeod, and Gobet .. McLeod is missing.\n\nAs the journal's focus is on fast publication, I would prioritise the comments on Method and Results.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7384",
"date": "08 Dec 2021",
"name": "Aznur Hajar Abdullah",
"role": "Author Response",
"response": "Dear Prof Els Boshuizen, We are greatly appreciative of the insightful comments and helpful suggestions that you have provided. Some of the issues are somewhat similar in term of the responses, so we encapsulated issue 1 and 3, in the last comments (comment no# 5). The following are our response on the five issues that you have highlighted: Thank you for proposing Schmidt and Moust’s paper, we had read the paper with great interest. Schmidt and Moust studied about what makes a tutor effective and we found some similarities in the line of argument, that also emphasizes the personal qualities of the tutor . In essence this study proposed, do not presume experts from similar ties would offer similar degree of scaffolding as their degree of scaffolding corresponds with the level of crystallised intelligence that they have . We have commented more detailed in comment #5 below ). * In the revised version later, we will incorporate more clearly on why t the theory of fluid and crystallised intelligence was used. In the original submission the codes were attached, but they were coded directly from Facebook communication ( all Facebook communications were the snapshots from Facebook and coded in ATLAS.ti). Despite the identities of all participants were cancelled and made anonymous , for copyright purposes, the F1000 reviewer recommended to transcribe the conversations as they cannot be published with any element associated to Facebook. *In the revised version, we will incorporate again the coding. To some extent we believe the ties matter as strong tie and weak tie with more working experiences who showed differing in levels of intelligence (fluid vs strong intelligence) - they were more accommodative to students' learning needs. Explaining about the tie per se seems incomplete to explain why not all weak tie experts behave in similar manner when scaffolding the students. Experts from Group 2 showed different scaffolding approach from experts from Group 1 and Group 3 . We have commented more detailed in comment #5 below ). Rather than looking at Bilalic and Gobet resonate differently from Kahneman’s, we opine that the arguments from these authors complement the findings of this study. Bilalic and Gobet resonate the flexibility of the experts is in accordance with the degree of fluid and crystallised intelligence that the experts have. This study showed that, experts with lesser working experiences tended to seek “help” or to rely on information provided by the students before they could fully utilised System 2 thinking to scaffold the students to deal with ill-structured problems. Although novices have to go through certain stages before they could pick up and put pieces of information into a meaningful context, your comments made us realised, the experts with less crystalised intelligence need to put pieces of information too. Interestingly, we view this as a pre-scaffolding preparation that experts from Group 2 in this study exhibited before they could devise an appropriate assistance to students. Your comment has enlightened us to propose future research to investigate the reciprocal role that students could play in scaffolding the experts’ thinking. In the revised version we will improve the clarity of the sentence to capture the above comments in the revised version. If you agree with the above comments, please let us know. Thank you again for your time in reviewing this manuscript."
}
]
},
{
"id": "97807",
"date": "08 Nov 2021",
"name": "Fauziah Sulaiman",
"expertise": [
"Reviewer Expertise Education: Physics/Science Education",
"Educational Technology",
"Higher Education",
"in-depth in Problem Based Learning Model. Physics: Non-Destructive Testing (Eddy-Current Testing Technique)"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall the article is well written and easy to follow. It is about the use of PBL in the Facebook platform to students' engagement in real-life activities by involving the business expert as the booster for them to really immersed in the issue they are facing. However, the weak and strong ties in this research are lacking with basic info, for example, why does the student need to choose by themself the business expert? Why not the researcher choose the business expert? Therefore the weak, strong, and weak+strong group setting maybe can be arranged. Having these totally different group settings can lead maybe different impactful outputs. Just a thought anyway.\n\nSo these are my comments on the statement that I commented as partly:)\nOther than that, all looks adequate.\nA few additional comments on the manuscript can be found here.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "97803",
"date": "09 Nov 2021",
"name": "Mohd Nazir Md Zabit",
"expertise": [
"Reviewer Expertise Business education",
"teacher pedagogy",
"thinking skills"
],
"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 aims to explore the problem-solving styles that the experts portrayed on Facebook based on their ties with the students.\nOverall, the methodology suits the research requirements. It has been clearly explained and easily understood by readers. The only concern is how the authors arrange and monitored the three closed Facebook groups with 12 final year management students, six business experts, and one instructor as the participants. Need a little bit of explanation.\nOverall, the manuscript has been written and prepared in a moderate writing style. The work is acceptable based on the suggestions given and should also be based on other assessors’ comments.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "97802",
"date": "23 Nov 2021",
"name": "Lillian Buus",
"expertise": [
"Reviewer Expertise Expertice in Problem-Based learning and education",
"knowledge about strong and week ties",
"from novice to expert (Dreyfuss and Dreyfuss)",
"Teaching with digital technologies and social media use"
],
"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 works with weak and strong ties in relation to PBL group-work inviting in experts to scaffold students learning.\n\nThis is an interesting and relevant research, although I miss a clear theoretical approach, as it seems the theory is not following through the article. The authors present in the introduction 'connectivism' but do not refer to this or their arguments in the introduction or the discussion. I also wish to stress that the first two references are placed wrong and that Siemens is missing an s (just to have some formats in place).\n\nWhat I would suggest to the authors, is to work a little more with the structure of the article as well. I miss a clear theoretical part, that also can be part of the argumentation in the discussion. So, choose only some of the theoretical approaches brought in, and go more in depth with these arguments.\n\nAnother part I would like the authors to consider is the figures. It might be good to structure the 'Excerption from the groups' after each other, as it becomes confusing to read the analysis 'in between' figures. I also miss the arguments for the statement: \"The explanations given by the experts in group 1 and 3 were also seen as more insightful compared to the guidance provided by experts in Group 2\" - I miss the \"Why\" and \"How\" arguments on this.\n\nI also would like the authors to elaborate more on the analysis and how they have conducted that e.g. with examples of parts that identified the expert’s roles. Also, for other being able to in details to replicate the research. Transparency is important, and there is a minor lack in this part.\n\nA part I also think is missing in the methods is the ethical consideration on using SoMe like Facebook for this. Not that it is wrong but I believe that there is some issue combined with this. What if an expert didn't have Facebook or would use this media for professional work issues? What about the right for information on Facebook? Other ethical issues could also be stressed. Just a notion on this could be expected as well when talking ethical issues.\n\nIt was positive to read that the authors took into consideration the sampling for the research, which is good. I think the research is interesting and I would like the authors to go more into this to gain more insights for this.\n\nGood work so far and just work on the combination of theoretical arguments and analysis/conclusion will give your article more strength.\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? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1076
|
https://f1000research.com/articles/10-1286/v1
|
15 Dec 21
|
{
"type": "Research Article",
"title": "Experimental study and modeling the tensile strength of 3D‐printed aluminium polylactic acid (PLA) parts using artificial neural networks",
"authors": [
"Chockalingam Palanisamy",
"Hong Kiat Aaron Tay Hong Kiat",
"Hong Kiat Aaron Tay Hong Kiat"
],
"abstract": "Background: High quality 3D printed products are in high demand, resulting in an increase in the production of 3D printed parts with precise tolerances, improved surface roughness, and overall durability. The processing parameters of 3D printers have a significant impact on the quality of 3D printed parts. Three-dimensionally printed parts must be durable, especially in terms of tensile strength, and its impact on the printer's process parameters must be investigated. Methods: Tensile test specimens were printed in the Makerbot 3D printer with aluminium polylactic acid (PLA) material. The three controllable input parameters taken into consideration were layer thickness, infill density and number of shells. The three levels for each of the respective parameters were 0.1mm, 0.2mm and 0.3mm for layer thickness; 2,3 and 4 for number of shells; 20% 40% and 60% for Infill density. Tensile testing was carried out on the specimens and data was tabulated. Using these data, an artificial neural network model was created using Matlab R2021b software’s neural network toolbox (alternatively Scilab can be used). Results: A high layer thickness (0.3mm) and a 40% infill density were found to be the most effective among all other parameters. The specimen with the lowest layer thickness of 0.1mm, four shells, and a 20% infill density had the highest tensile strength. With the tensile test data, a Matlab ANN model was developed. Validation was done by comparing the values obtained from the model with the experimental data by using random layer thickness, infill density, and number of shells. Conclusions: In conclusion, higher layer thickness has lower tensile strengths. However, as the number of shells and infill density increases, the tensile strength increases. In summary an ANN model was successfully developed and validated to predict 3D printed aluminium parts.",
"keywords": [
"3D Printing",
"ANN",
"Aluminium PLA",
"Tensile Strength"
],
"content": "Introduction\n\nAdditive manufacturing processes such as 3D printing are widely used today in many industries. 3D printing has become more widely used in industries, increasing the number of consumers in need of 3D printed products of high quality.1 As a result of increased competition, 3D parts with more precise tolerances, better product finish, and overall durability have become increasingly popular. Despite the fact that 3D printing costs are on the decline, part quality issues such as integrity, strength and aesthetics are still a concern.2 Because of this, industries have been driven to continuously improve quality control of their products. These quality measures are very important to mechanical parts because it affects the cooperation of parts together, working accuracy, physical properties and chemical properties altogether. 3D printing industries rely on these qualities to produce better-looking and more functional parts while also saving money by reducing the amount of time needed to manufacture the parts.3 The parameters that are taken into considerations are layer thickness, infill density and number of shells.4 The product's tensile strength is a critical factor to take into account. In this study, a central composite design experimental plan was developed with three influencing input parameters, namely infill density, layer thickness and number of shells. Aluminium polylactic acid (PLA) materials were used as a work material. Tensile test was conducted on the specimen and recorded. Using the data, an artificial neural network (ANN) model was developed to predict the tensile strength of new combination of parameters, and a validating test carried out on the model.\n\n\nMethods\n\nThis study was conducted in November 2020. A design of experiment (DOE)/Central Composite Design (CCD) experiment plan was designed with three input parameters (layer thickness, infill density and number of shells) shown in Figure 1. There are eight corners, six face centers, and one center, for a total of 15 specimen points.4,5 Table 1 shows the three levels of parameters. Table 2 displays the experiment plan as well as the test results.\n\nTensile test specimens were printed in the Makerbot 3D printer. PLA filament mixed with 15% aluminium powder (Al-PLA- Fabbxible, 1.75 mm diameter) was used as work material. One tensile test was carried out using the Instron 3360 series dual column tabletop equipment. The results were captured using Instron Bluehill- Universal 3 software. American society for testing of materials (ASTM). D-638 standard size was used to prepare the specimen.\n\nArtificial neural networks (ANN) are artificial computing systems that mimic biological neural networks, which are similar to the human brain. The system has self- learning capabilities to perform tasks or produce better results.6 Using the data, an ANN model was developed to predict the tensile strength of newer combinations of input parameters, and a validating test carried out on the model. Matlab R2021b neural network software (Scilab is an open-source alternative) was used to create a neural network with the printer process parameter and tensile strength data (Table 2).\n\nIn order to develop the ANN model, the experimental data were imported into Matlab software. With the deep learning toolbox feature, a framework for creating and designing neural networks was made. Whilst giving the option to import, create and export networks and data, it can also generate a neural network system which can be designed, simulated and analysed.\n\nAll procedures used in this project have been approved by Research Ethics Committee (REC) Multimedia University (EA2892021). This work does not involve data collection from human or animal experiments or vulnerable communities.\n\n\nResults and discussion\n\nThere are four specimens in Figure 2 that stand out as having the highest values of tensile strength. Other specimen includes 1, 3, 5 and 7. They have the same layer of thickness (0.1 mm). This indicate that the lower the layer thickness the higher the tensile strength. As an example, if we look at specimens 13, 14, and 15, they all have the same number of layers (0.3 mm) and three shells, but different infill density levels. Specimen number 13 that has the lowest infill density of 20% appears to have the lowest tensile strength of 0.71 kN. As a result, the breaking load decreases as infill density decreases. There are no differences in layer thickness or infill density between specimens 1 and 3, but there is a discrepancy in the shell count between specimens 1 and 3. In spite of the fact that specimen 3 has a much higher number of shells than specimen 1, it has a slightly higher breaking load. The same is true for specimens 2 and 4, which have similar values of layer thickness (0.3 mm) and infill density (20%). Specimen 4 have a very slight increase of breaking load compared specimen 1, even though specimen 4 has a much higher number of shells compared to specimen 2. Specimens 5 and 7, which have similar values of layer thickness (0.1 mm) and infill density of 60%. Specimen 7 also has a very slight increase of breaking load compared specimen 5, even though specimen 7 has a much higher number of shells compared to specimen 5. This means that the values of layer thickness and infill density have a significant impact on the value of tensile strength. However, the number of shells does not the effect the variation of breaking load in test specimens. The tensile strength increases with decreasing layer thickness. The specimen's tensile strength increases as the infill density increases.5\n\nAn ANN model was created as shown in Figure 3, by entering input such as layer thickness, number of shells and infill density and tensile strength data as a target data.\n\nErrors in validation and training can be used to gauge a trained network's performance as a whole. Performing a regression plot between the network response and the targeted values, as shown in Figure 4, is one way to achieve this goal. We can tell if the neural network is desirable or not by generating the regression plot. The regression plot depicts the relationship between a network response variable (output) and target variables. If we had a perfect fit, where outputs exactly equal to targets, the slope would be of value “1” and the y-intercept would be at point (0, 0). This condition is considered to be desirable, which means a good correlation of targeted values to output values. Vice versa, if the slope is not close to value “1”, then it can be considered as not desirable; such a condition is shown in Figure 4a. If it is not desirable, we can retrain the network by closing the window and clicking on train network again until we get a regression plot’s value for all that is close to the value “1” as shown in Figure 4b. As a result of oscillating between input and output values, the neural network learns and repeats the process. This will eventually give a better regression model close to the value “1”. It is a good idea to train several networks to ensure that a network with good generalization is found. Figure 4b shows a good regression plot. According to Figure 4, the open circles represent the values of network output plotted against the goals. The best fitted slope is indicated by the dashed line and the solid line indicates the fitted slope generated by the open circles.\n\nAccording to Figure 4a, Matlab's first trained network isn't ideal because the regression slope value for all is 0.94767 and the y-intercept isn't close to 0. By retraining the network, we are able to get results such that in Figure 4b, which is our desirable regression. Next simulating by going to the simulate tab, selecting the inputs and clicking simulate network. Using the developed model tensile strength was predicted the new set of input parameters and tabulated in Table 3.\n\nTo validate the developed ANN model, 5 new test specimens were fabricated as shown in Table 3. The five test specimens were then subjected to a tensile test, and the results were tabulated. Based on the table, the specimen with the lowest layer thickness has the highest tensile strength with 1.05kN. This can be validating with what we have discussed previously where the lower the layer thickness, the higher the tensile load. The percentage difference of experimental values and theoretical values for all the specimens are less than 5%.\n\nAccording to Table 3, the percentage difference between experimental data and ANN model predicted data for all specimens is less than 5%, which proves the model's validity and reliability.\n\n\nConclusions\n\nAn ANN model was successfully developed and validated using Matlab to predict the 3D printed aluminium part data. The three variables of layer thickness, number of shells, and infill density have been shown to affect the tensile strength of the 3D printed specimens. The specimen with the lowest layer thickness of 0.1 mm, four shells, and a 20 percent infill density had the highest tensile strength of 1.12 kN, based on the results of the tests. In addition, specimen 13 has the lowest tensile strength of 0.71 kN when compared to specimens 14 and 15, which all have the same layer thickness (0.3 mm) and number of shells (3) but different infill density. For this reason, the thicker layers have lower tensile strengths. However, as the number of shells and infill density increases, the tensile strength increases. In summary, the 3D printed part with the lowest layer thickness, highest infill density, and most shells has the highest maximum tensile strength, according to the research. A comparison of predicted and experimental results allowed us to verify the accuracy of the ANN model.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgements\n\nAuthors acknowledge Mr. Wan Johannes, Senior lab technician, Faculty of Engineering and Technology, Multimedia University, Melaka, Malaysia for his help during experiments. Furthermore, a thank you to the Research Synergy Foundation for the recommendations and support.\n\n\nReferences\n\nNgo TD, Kashani A, Imbalzano G, et al.: Additive manufacturing (3D printing): A review of materials, methods, applications and challenges. Compos. Part B. 2018; 143: 172–196. Publisher Full Text\n\nRahim TNAT, Abdullah AM, Md Akil H: Recent developments in fused deposition modeling-based 3D printing of polymers and their composites. Polym. Rev. 2019; 59(4): 589–624. Publisher Full Text\n\nMehrpouya M, Dehghanghadikolaei A, Fotovvati B, et al.: The potential of additive manufacturing in the smart factory industrial 4.0: A review. Appl. Sci. 2019; 9(18): 3865. Publisher Full Text\n\nPalanisamy C, Krishnan GK: Experimental classification and response surface modelling of compression property of 3D printed polylactic acid parts. AIP Conference Proceedings. AIP Publishing LLC.; 2021; Vol. 2339(No. 1): p. 020070\n\nPalanisamy C, Chinnasamy N, Muthu K: No. 2 Influence of Process Parameters on Rapid Prototype Part Using Response Surface Methodology. J. Eng. Techn. App. Phys. 2019; 1(1): 4–7. Publisher Full Text\n\nAbiodun OI, Jantan A, Omolara AE, et al.: State-of-the-art in artificial neural network applications: A survey. Heliyon. 2018; 4(11): e00938. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "115355",
"date": "06 Jan 2022",
"name": "Mahros Darsin",
"expertise": [
"Reviewer Expertise FDM 3D printing using metal content filaments"
],
"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 is trying to apply an Artificial Neural Network (ANN) to optimize the variable combinations which will result in the highest tensile strength of the 3D printed parts using aluminium-PLA filament. Some useful information is provided in the introduction. However, it lacks references about using ANN by other researchers, such as Yadav et al. (2020)1 and Mahmood et al. (2020)2.\nThe presentation of Table 2 needs to be improved, such as by aligning the number at the X-axis to the bar.\nThere are some errors in the description of results and discussion. For example, the minimum of tensile strength is shown by experiment no. 11 not no. 13. The same error is repeated at the conclusion. The error is also clear when comparing the result of experiments no. 2 and 4. Mistakenly, it is written as experiment no. 1.\n\nStatement regarding either value 1 or 0, which is considered as not desirable needs to be clarified when describing the ANN. I found two statements contradicting regarding it.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7972",
"date": "18 Mar 2022",
"name": "Palanisamy Chockalingam",
"role": "Author Response",
"response": "Reviewer comment: The presentation of Table 2 needs to be improved, such as by aligning the number at the X-axis to the bar. Reply: Experiment plan is designed with face centered central composite design and table is left aligned. Reviewer comment: There are some errors in the description of results and discussion. For example, the minimum of tensile strength is shown by experiment no. 11 not no. 13. The same error is repeated at the conclusion. Reply: This comparison for the layer thickness of 0.2 mm, for specimens 13, 14 and 15. Reviewer comment: The error is also clear when comparing the result of experiments no. 2 and 4. Mistakenly, it is written as experiment no. 1. Reply: Experiment results of 2 and 4 is for layer thickness of 0.3 mm. So the variation is obvious. Reviewer comment: Statement regarding either value 1 or 0, which is considered as not desirable needs to be clarified when describing the ANN. I found two statements contradicting regarding it. Reply: These statements explain the how to reach the closeness to the desired result and to explain the all procedures followed in this research."
}
]
},
{
"id": "126037",
"date": "09 Mar 2022",
"name": "John Kechagias",
"expertise": [
"Reviewer Expertise Materials and manufacturing processes"
],
"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 presents some new data. The reviewer recommends the following to increase the manuscript quality:\nIntroduction. The literature review is inadequate. This research deals with PLA/aluminium FFF 3D printing process parameters influence on the mechanical response of 3D printed parts. Additionally, an ANN model is adopted to model the effects of the parameters. So, literature should be include reference papers like the following articles of mine:\nKechagias et al. (2022a)1, about key parameters of the FFF process. Kechagias et al. (2022b)2, about NN parameter optimization.\n\nThe authors should critically review the used parameters.\n\nThe same about the ANN topology parameters selection.\n\nThe authors should also analyze why they keep the other 3D printing parameters constant and why they used the specific values.\n\nThe authors should present the parameters' effects on mechanical response and generalize the results in other materials.\n\nSEM images are needed to see the porosity of the parts. Parts weight should be reported too in table 2 and the strength modulus of elasticity E.\nSpecific\nIn the 'abstract,' the authors claimed: \"The specimen with the lowest layer thickness of 0.1mm, four shells, and a 20% infill density had the highest tensile strength...\" and then, \"However, as the number of shells and infill density increases, the tensile strength increase…\" - These two sentences are confusing. Which is correct?\n\nProofread the document carefully. E.g., 3D printed parts and not '3D parts.'\n\nUse more references in the introduction. Document better each sentence you use.\n\nTable 2. Please use the elasticity module E and strain at sB to better show the specimens' mechanical response.\n\nDetails of the 3D printing parameters used in the experiment are missing. Please explain why only the LT, NS, and ID are used in this research, as it is critical for the scope of the study.\n\nExplain if you used normalization for inputs and outputs (for the ANN model) and, if not, why?\n\nDetails of ANN training and stop criteria are missing.\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": "7973",
"date": "18 Mar 2022",
"name": "Palanisamy Chockalingam",
"role": "Author Response",
"response": "Reviewer comment: Introduction. The literature review is inadequate. This research deals with PLA/aluminium FFF 3D printing process parameters influence on the mechanical response of 3D printed parts. Additionally, an ANN model is adopted to model the effects of the parameters. So, literature should be include reference papers like the following articles of mine: Kechagias et al. (2022a)1, about key parameters of the FFF process. Kechagias et al. (2022b)2, about NN parameter optimization. Author’s response: Your feedback is duly noted. My article was written much earlier to the reference materials. I will use these references for future articles. Reviewer comment: The authors should critically review the used parameters. Author’s response: The parameters were selected based on literature (referenced) and machine specifications. Reviewer comment: The same about the ANN topology parameters selection. Author’s response: The parameters were selected based on literature (referenced) and machine specifications. Reviewer comment: The authors should also analyze why they keep the other 3D printing parameters constant and why they used the specific values. Author’s response: The parameters were selected based on literature (referenced) and machine specifications. Experiment plan was designed based on face centred central composite design (FC-CCD). So the parameter combinations have to follow the design. Reviewer comment: The authors should present the parameters' effects on mechanical response and generalize the results in other materials. Author’s response: This research was carried out on specific material and reported, other material comparison was not under the parameters of my research. Reviewer comment: SEM images are needed to see the porosity of the parts. Parts weight should be reported too in table 2 and the strength modulus of elasticity E. Author’s response: This research study was conducted to study the effects of the combination of input parameters on tensile strengths of the material, so, I believe SEM analysis is not necessary. Specific Reviewer comment: In the 'abstract,' the authors claimed: \"The specimen with the lowest layer thickness of 0.1mm, four shells, and a 20% infill density had the highest tensile strength...\" and then, \"However, as the number of shells and infill density increases, the tensile strength increase…\" - These two sentences are confusing. Which is correct? Author’s response: Both are correct, because the study is based on the experiment plan - face centred central composite design. Reviewer comment: Proofread the document carefully. E.g., 3D printed parts and not '3D parts.' Author’s response: Duly noted. Reviewer comment: Use more references in the introduction. Document better each sentence you use. Author’s response: Duly noted for my future articles. Reviewer comment: Table 2. Please use the elasticity module E and strain at sB to better show the specimens' mechanical response. Author’s response: Duly noted for my future articles Reviewer comment: Details of the 3D printing parameters used in the experiment are missing. Please explain why only the LT, NS, and ID are used in this research, as it is critical for the scope of the study. Author’s response: The parameters were selected based on literature (referenced) and machine specifications. Reviewer comment: Explain if you used normalization for inputs and outputs (for the ANN model) and, if not, why? Author’s response: I believe normalization is not necessary because these experiments followed face centred central composite design. Reviewer comment: Details of ANN training and stop criteria are missing. Author’s response: It has been explained in the methods section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1286
|
https://f1000research.com/articles/9-1271/v1
|
23 Oct 20
|
{
"type": "Research Article",
"title": "Comparison of temporal fine structure sensitivity and concurrent vowel perception between children with and without reading disability",
"authors": [
"Arivudainambi Pitchaimuthu",
"Eshwari Ananth",
"Jayashree S Bhat",
"Somashekara Haralakatta Shivananjappa",
"Arivudainambi Pitchaimuthu",
"Eshwari Ananth",
"Jayashree S Bhat"
],
"abstract": "Background: Children with reading deficits (RD) exhibit difficulty in perceiving speech in background noise due to poor auditory stream segregation. There is a dearth of literature on measures of temporal fine structure sensitivity (TFS) and concurrent vowel perception abilities to assess auditory stream segregation in children with reading deficits. Hence the present study compared temporal fine structure sensitivity (TFS) and concurrent vowel perception abilities between children with and without reading deficits. Method: The present research consisted of a total number of 30 participants, 15 children with reading deficits (RD) and fifteen typically developing (TD) children within the age range of 7-14 years and were designated as Group 1 and Group 2 respectively. Both groups were matched for age, grade, and classroom curricular instructions. The groups were evaluated for TFS and concurrent vowel perception abilities and the performance was compared using independent ‘t’ test and repeated measure ANOVA respectively. Results: Results revealed that the children with RD performed significantly (p < 0.001) poorer than TD children on both TFS and concurrent vowel identification task. On concurrent vowel identification tasks, there was no significant interaction found between reading ability and F0 difference suggesting that the trend was similar in both the groups. Conclusion: The study concludes that the children with RD show poor temporal fine structure sensitivity and concurrent vowel identification scores compared to age and grade matched TD children owing to poor auditory stream segregation in children with RD.",
"keywords": [
"Reading deficits",
"Temporal fine structure sensitivity",
"Concurrent vowel perception",
"auditory stream segregation."
],
"content": "Introduction\n\nReading is defined as a cognitive process by which one derives meaning from printed symbols1. Reading ability in children relies on the integration of rudimentary perceptual abilities with higher-order linguistic function2. It is estimated to be impaired in 5 to 17% of school-going population and observed as the most common neurodevelopmental disorder in children3. Children with reading disability (RD) demonstrate difficulty in learning to read and spell, despite having adequate intelligence and conventional instruction. Although the pathophysiology of RD is unknown, some hypothesize that RD emerges due to the deficits in encoding, representing, and processing phonological information4–6. In other words, children with RD show difficulties in acquiring the ability to relate language-specific written codes such as letters to corresponding spoken codes such as phonemes, resulting in word decoding deficits, which are the most palpable impairment in majority of children with RD7–9. The processing of phonological information is determined by crucial aspects of auditory speech perception. Perceiving and interpreting auditory information is one of the factors that affect language acquisition and academic performance in children with normal hearing ability. Hence, the auditory perceptual abilities are important for reading as well as for exploring different phonological features. Tallal10–12 reported that receptive language is processed via the auditory system and the deficits in auditory perceptual skills results in impaired phonology, leading to difficulty in reading.\n\nAuditory processing plays a significant role in the acquisition of oral-aural language in children. Accurate extraction of spectral (frequency information) and the temporal (timing) cues from the speech is essential for the meaningful representation of phonological cues at higher levels. The auditory processing deficit that disrupts the coding of these acoustic cues may lead to inadequate representation of speech sounds. Studies have been done to identify the underlying cause of dyslexia, which gave rise to many theories. An influential hypothesis by Tallal, Merzenich, Miller, & Jenkins13 states that, any deviant recognition of fast acoustic events in the speech hampers the normal development of phonological systems. Various research findings support this hypothesis and indicate that poor readers exhibit difficulty in the recognition of rapid acoustic events in speech and non-speech signals12,14. Tallal7 reported that children with RD have difficulty in perceiving auditory stimuli with short duration and sounds that occur in rapid series. Such a deficit in auditory processing may compromise the temporal analysis of speech at the phoneme level, thus affecting in the development of phoneme representations. These limitations pose specific challenges to children with RD to acquire both oral as well as the written language.\n\nAuditory processing deficit in children with RD also manifests as speech perception difficulties15. For example, Hazan16 reported that 30% of children with dyslexia exhibited speech perception deficits. Similarly, Manis et al.17 also found that 28% of individuals with dyslexia showed a deficit in categorical perception for the voicing continuum. Tasks employed to assess categorical perception typically utilize optimal listening conditions. In such conditions, specific phoneme identification deficits would be compensated by the higher functions17–19. That may be the possible reason for the prevalence of categorical perception deficits only in a small set of the population with dyslexia. However, when the perceptual ability was assessed in less than optimal listening conditions, the majority of the individuals with dyslexia exhibit perceptual deficits. Blomert and Mitterer20 reported that individuals with dyslexia exhibit considerable difficulty in the perception of synthetic speech when compared to natural speech. Similarly, individuals with dyslexia demonstrate more difficulty in perceiving speech in the presence of noise despite having good perception abilities in quiet conditions8,21.\n\nGenerally, the difficulties to perceive speech in the presence of background noise are one of the common complaints of the children with auditory processing deficits15,22–24. The ability to perceive speech in the presence of background noise necessitates the auditory system to segregate the background noise from the target speech signal, and the process is reffered to as auditory stream segregation25. The critical acoustic cue that helps in auditory stream segregation/formation is a temporal fine structure (TFS). TFS helps to segregate the target speech and background noise into two separate streams26. There is a dearth of research that investigates auditory stream segregation abilities among children with RD. Few attempts have been made to investigate the perception of TFS by individuals with RD27. In this study, iterated ripple noise (IRN) pitch perception was considered as the measure of TFS sensitivity. However, recent investigations have shown that IRN pitch perception does not reflect the TFS sensitivity as spectral modulations mediate the perception of IRN pitch. Hence, TSF sensitivity in children with RD needs to be investigated using a validated method. Sek and Moore28 suggested TFS1 test as a valid method that can be used to study TFS sensitivity. Therefore, the TFS1 method was used in the present study to assess the TFS sensitivity in children with RD. Additionally, auditory stream segregation can be studied reliably by using the most commonly considered paradigm, such as concurrent vowel identification paradigm29,30, which has high relevance to the perception of speech in the presence of noise. Hence, the present study compares the performance of TFS1 and concurrent vowel identification paradigm between children with reading disabilities and typically developing children. The study also explores the association between TFS1 and concurrent vowel paradigm in children with RD and typically developing (TD).\n\n\nMethod\n\nThe present study employed a cross-sectional study design and a non-random convenient method of sampling to recruit the participants. The study was carried out in a school located in Mangalore, a city of Dakshina Kannada District of coastal Karnataka. The study was conducted between December 2018 and January 2019. The study proceeding was approved by the Institutional Ethics Committee of Kasturba Medical College, Mangalore. In order to avoid the variability in curricular material and method of teaching, all the participants were selected from a single school with the instructional medium being the Kannada language and the school curriculum affiliated to the Karnataka state board. Initially, permission from the school administrative authority was obtained to conduct the study on children within the school premises. Later, parents of participants were informed about the nature of the study, and written consent was obtained before initiating the study.\n\nThe present research consisted of a total number of 30 participants, 15 children with RD, and 15 TD children, within the age range of 7–14 years, who were designated as Group 1 and Group 2, respectively. The 15 children with RD were pooled from Grade II (N=1), Grade III (N=1), Grade IV (N=2), Grade V (N=2), Grade VI (N=5), and Grade VII (N=4) within the age range of 7.6 to 8.6 years, 8.7 to 9.6 years, 9.7 to 10.6 years, 10.7 to 11.6 years, 11.7 to 12.6 years and 12.7 to 13.6 years respectively. A similar pool of TD children was selected to match the age and Grade of RD children. The Linguistic Profile Test in Kannada31 was used to ascertain age-appropriate language development in both the groups. The Reading Acquisition Profile in Kannada32 was administered to determine the reading abilities of children from both the groups. The participants with the performance falling below 2SD of mean scores of TD criteria were classified as RD. All participants had hearing sensitivity within normal limits as their hearing thresholds ≤25 dBHL at audiometric octave frequencies (250 to 8000 Hz). None of the participants had gross otologic and neurologic deficits. Intially, the class teachers was requested to rate the children’s performance based on their perception on reading, writing, spelling, arithmatic skills, oral language comprehension, and expression skills according to the Grade level and in comparison with all other children in the classroom in every domain of language and literacy skills using a 5-point Likert rating scale (0 = poor, 1 = below average, 2 = good, 3 = very good, 4 = outstanding). Parents of the selected children were explained about the study and written consent was obtained from them. The children who were rated as poor and below average were further assessed for language and reading assessment to confirm the presence of RD based on the study criteria.\n\nThe following section explains the process of signal processing for the stimuli development and, also administration procedures of TFS sensitivity and concurrent vowel identification task measures. Each procedure was performed once per child.\n\nSignal processing. A complex harmonic tone (H) with the fundamental frequency (F0) of 100 Hz was created with a sampling frequency of 44,100 Hz. Inharmonic complex tone (I) was created by adding a fixed frequency difference (∆f) to the harmonic complex tone. Participant’s TFS sensitivity was estimated as minimum ∆f that is required to discriminate ‘H’ and ‘I.’ All the components of both harmonic and inharmonic complex tones had equal amplitudes. Partials of the ‘H’ and ‘I’ had random phases. Spectral content between 9th and 13th harmonics was retained while all others were filtered out using a 5th order digital butter-worth filter to reduce cues related to the difference in excitation patterns. The participant’s ability to discriminate between harmonic and inharmonic complex was assessed as a function of ∆f. Threshold equalizing noise (TEN) was presented along with H and I tones to avoid the audibility of combination tones.\n\nProcedure. The stimuli were presented from a laptop (TOSHIBA, with intel core i5 processor) routed through the sound card (creative sound blaster X-fi USB 2, 24-bit digital-to-analog converter) and given through circum-aural stereo headphones (Sennheiser HD280Pro). To estimate TFS sensitivity, a transformed up-down procedure (2-down 1-up) with two intervals, two alternatives forced-choice (2IAFC) task was used. The stimuli were designed and presented through the laptop. For the TFS task, participants were presented with two intervals, target, and non-target interval. The non-target interval consisted of four harmonic complex tones in sequence with the inter-stimulus interval of 100 milliseconds (HHHH). In the target interval, two harmonic and two inharmonic complex tones were presented alternately with the inter-stimulus interval of 100 milliseconds (HIHI). The participant’s task was to identify the interval containing the HIHI pattern. The target and non-target intervals were presented in a random sequence, and the gap between the intervals was 500 milliseconds. Participants responded by clicking on the push-buttons appearing on the computer screen. The participants pressed the push-button “1” if the target was present in the first interval, and pressed push-button “2” if the target was present in the second interval. The test started with ∆f of 50 Hz, and the ∆f was varied adaptively in 2 Hz step size. For every two consecutive positive response, ∆f was reduced by 2 Hz, and for every single negative response, ∆f was increased by 2 Hz. Midpoints of the last six reversals from the total eight reversals were averaged to estimate the thresholds. If the ∆f values exceeded 50 Hz, then 40 trials were presented at ∆f of 50 Hz, and total correct response scores were obtained.\n\nSignal processing. Five steady-state vowels /a/, /i/, /e/, /u/, /o/ was synthesized at the sampling rate of 44,100 Hz, using Klatt synthesizer. Each vowel was synthesized with F0 of 200 Hz. All five vowels were synthesized again with different F0 which was corresponding to 1, 2, and 4 semitones increase from base F0. So, this resulted in a total of 20 vowels. Each vowel had a duration of 270 msec with 20 ms raised cosine onset/offset ramps. Concurrent vowel pairs were created by pairing vowels with each other across different vowels and F0 conditions (5 vowels and 4 F0 conditions). The same vowel was never present in a pair, even if the F0 was different. This pairing resulted in combinations of vowels with the F0 difference of 0, 1, 2, and 4 semitones between them.\n\nProcedure. The stimuli were presented using the same instruments indicated for the measurement of TFS sensitivity. Stimuli were presented at most comfortable level (MCL) as set by the participant before the test. The participants were asked to identify both the vowels that occurred during each presentation. Participants responded on a forced-choice paradigm where a response box consisting of all the five vowels appeared on the screen. Participants were instructed to respond by clicking on the appropriate buttons. Feedback was not provided during the session. Every vowel pair was presented 20 times. Percentage of correct identification of both vowels (double correct scores) and the percentage of correct identification of at least one vowel was calculated (single correct scores). Single correct scores were considered for further analysis as most of the children could not identify both the vowels.\n\nThe results of the present study was analyzed using SPSS v17.0 statistical analysis software. The performance of children with RD on TFS1 was compared with the performance of TD children using a parametric independent ‘t’ test. Similarly, the performance of children with RD on concurrent vowel identification tasks was compared with TD children using the parametric repeated measure ANOVA with subsequent post-hoc pair-wise comparison using Bonferroni’s test. The association between the performance of TFSI with concurrent vowel identification abilities among RD and TD was done using Pearson’s correlation co-efficient.\n\n\nResults\n\nThe present study aimed to investigate the auditory stream segregation abilities of children with RD in comparison with TD using TFS1 and concurrent vowel identification task. Underlying data from each participant is available at Harvard Dataverse33.\n\nIn the current study, the TFS sensitivity was assessed as the maximum ∆f that is required to differentiate harmonic and inharmonic complex tones. However, in most of the participants, the ∆f value exceeded 50% of the F0. Hence, the percentage of correct responses for differentiating harmonic and in-harmonic was measured for the ∆f value of 50% of the F0. The percentage of correct scores in both the RD (w = 0.90, p = 0.10) and TD (w = 0.91, p = 0.13) groups was normally distributed. A parametric independent sample t-test was done to investigate the whether the percentage of correct response for differentiating harmonic and in-harmonic complex tones of children with RD was different from TD children. The analysis revealed that there was a significant difference in the percentage of the correct score between the children with RD and TD children (t28 = -4.31, p < 0.001). The percentage of the correct score of children with RD was significantly less than that of the TD children. This result suggests that children with RD have poorer TFS sensitivity than TD children. The mean and standard deviation of the percentage of correct scores for differentiating the harmonic and inharmonic complex tone is depicted in Figure 1.\n\nIn the current study, the concurrent vowel identification task was used as a measure to assess the stream segregation ability. The children’s ability to correctly identify the two concurrently presented vowels was measured as a function of the F0. Since the children could not identify both the vowels, single correct scores were considered. Total correct scores for each F0 difference condition were measured, and these scores were compared between children with RD and TD children. Repeated measure ANOVA was done to investigate the main effect of reading ability (RD and TD) and F0 difference (0, 1, 2, and 4 semitone difference) on concurrent vowel identification. For the analysis, reading ability served as the between-subject factor, and the F0 difference served as a within-subject variable. The analysis revealed a significant main effect of F0 difference on vowel identification (F (3,84) = 3.302, p=0.02). Effect of reading ability on concurrent vowel identification was also significant (F (1,28) = 13.84, p<0.001). Overall concurrent vowel identification scores of children with RD were significantly poorer than TD children. There was no significant interaction found between reading ability and F0 difference (F (3,84) = 0.23, p=0.88), suggesting that the trend was similar in both the groups. The mean and standard deviation of the consonant vowel identification at different semitones for both the group is depicted in Figure 2.\n\n\nDiscussion\n\nThe present study investigated the auditory stream segregation abilities of children with RD in comparison with TD using TFS1 and concurrent vowel identification tasks. The TFS sensitivity of children with RD and TD was assessed using the TFS1 test28. Statistical analysis revealed that children with RD have significantly poor TFS sensitivity when compared to TD children. In the human auditory system, TFS is represented by synchronous neural discharge, where the TFS information depends on the phase-locking to individual cycles of the stimulus carrier waveform (Moore, 2008). Some electrophysiological evidence has indicated a weak phase-locking ability in individuals with a learning disability34. Frequency following response for speech stimulus has shown reduced phase locking to speech cues such as first formant frequency in individuals with a learning disability35. Delay in neural timing leading to poor phase locking in children with learning disability has also been demonstrated in various other studies35–40. In the current study, TFS sensitivity was assessed for the ability to discriminate the harmonic and in-harmonic complex tone as the function ∆f, wherein, ∆f used was 50% of F0 of complex harmonic tone. For such difference, the phase-locking mediates the discrimination ability28. Reduced phase-locking ability present in children with RD could be the reason for the poor TFS sensitivity observed in the current study.\n\nIn the current study, concurrent vowel identification was used as a measure of auditory stream segregation. Individuals were presented with a concurrent vowel (two vowels presented simultaneously) pairs, and their ability to identify the two vowels as a function of F0 difference was measured. Total correct scores for correctly identifying both the vowels, or at least a single correct vowel, were calculated. Since most of the participants failed to identify both the vowels correctly, single correct scores were considered for further evaluation. Total correct scores were significantly poorer for children with RD than TD children, suggesting that children with RD exhibit poor stream segregation ability. The perception of concurrent vowels depends on two cues, that is, F0 and formant difference. When the two vowels differ in F0, phase-locking for these F0 cues plays a significant role in segregating both the vowels41. However, when the F0 is the same, phase-locking to the formant difference plays a vital role in differentiating the two vowels. Phase locking for the F0 and formant difference depends on the TFS sensitivity. Results revealed that children with RD have poorer TFS sensitivity than TD children. Poor TFS sensitivity could be because of the weak phase-locking ability in children with RD.\n\nAuditory stream segregation ability was assessed using concurrent vowel identification method. The children’s ability to correctly identify the two concurrently presented vowels was measured as a function of the F0. Total correct scores for each F0 conditions were measured, and these scores were compared between the two groups of children. The repeated measure ANOVA was conducted to investigate the main effect of reading ability and F0 difference on concurrent vowel identification. The analysis revealed a significant main effect of F0 difference in vowel identification. The effect of reading ability on concurrent vowel identification was also significant. Overall concurrent vowel identification scores of children with RD are significantly poorer than TD children, suggesting poor stream segregation ability in children with RD. This could be because of the poor TFS sensitivity and poor selective attention ability as the TFS sensitivity, and selective attention plays an important role in stream segregation.\n\n\nConclusion\n\nBased on the current findings, it can be concluded that children with RD show impairment in auditory stream segregation as they performed significantly poorer than TD children on both TFS and concurrent vowel identification measures. The outcome of the current study helps to understand the underlying mechanism responsible for speech perception deficits seen in children with reading disabilities. Results of the current study will lead to further research on developing rehabilitation strategies and assistive device selection.\n\n\nData availability\n\nHarvard Dataverse: Temporal processing data. https://doi.org/10.7910/DVN/XGTMAJ33.\n\nFile ‘Temporal fine structure sensitivity (TFS) and Concurrent Vowel Perception in Reading disability’ contains TFS and CVP scores for all children included in this study.",
"appendix": "Author contribution\n\nSomashekara Haralakatta Shivananjappa: Formal analysis, methodology, project administration, resources, writing-review & editing, & writing- original draft preparation.\n\nEswari Ananth: Formal analysis, investigation, project administration, resources, writing- original draft preparation\n\nJayashree S. Bhat: Supervision, visualization, writing- review & editing.\n\nArivudainambi Pitchaimuthu: Conceptualization, formal analysis, data curation, methodology, software, supervision, visualization, writing- review & editing.\n\n\nReferences\n\nKamhi AG, Catts HW: Toward an Understanding of Developmental Language and Reading Disorders. J Speech Hear Disord. 1986; 51(4): 337–47. PubMed Abstract | Publisher Full Text\n\nSchlaggar BL, McCandliss BD: Development of Neural Systems for Reading. Annu Rev Neurosci. 2007; 30(1): 475–503. PubMed Abstract | Publisher Full Text\n\nWysocka A, Lipowska M, Kilikowska A: Genetics in solving dyslexia puzzles. 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}
|
[
{
"id": "75988",
"date": "08 Feb 2021",
"name": "Vijaya Kumar Narne",
"expertise": [
"Reviewer Expertise Speech production and perception",
"Voice Sciences",
"Event-related potentials"
],
"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 studies the temporal fine structure and concurrent vowel perception in normal-hearing and Dyslexic children. The manuscript is well written with sufficient review and the methods employed are appropriate. I have some major issues and minor comments regarding the current version of manuscript.\n\nMajor comments:\n\nIntroduction largely concentrates on studies from USA/EU data, not much data from Indian. In our view, it is important as the phoneme-graphic correspondence is significantly different from English. Further, auditory processing impairment is correlated with VOT from western data. This cannot be directly implied for the same in the Indian population as VOT properties of Indians are very different. So, I feel that Introduction needs more specific to the population under study.\n\nAre the results of the TFS-1-test reliable for the age range under study? because the TFS values are poor compare to the literature. From the description in the present study, it is difficult to understand if the results are reliable. Further, there is a published study cited or that available none adopted TFS-1 test many adopted TFS-LF. This needs to be clarified.\n\nThe concurrent vowel identification task looks simple discrimination task, and it is far from auditory stream segregation. The author needs to provide evidence that such a task is considered as auditory stream segregation.\n\nMinor Comments:\nIntroduction-Para-1: Authors provide the % of RD from the western population. It would be more appropriate if they provide the same from the Indian population.\n\nIntroduction-Para-1: Impaired phoneme-grapheme correspondence impairment varies largely with Language. As English is complicated with reference to phoneme-grapheme correspondence, compare to Indian languages.\n\nMethod-TSF-test: Did the authors adopted the procedure developed by Prof. Moore or they used software developed by them. It is not clear from the description.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7496",
"date": "15 Dec 2021",
"name": "Somashekara Haralakatta Shivananjappa",
"role": "Author Response",
"response": "We thank the reviewers for the comments. Following are the response to the reviewer's comments. Comment 1: Introduction largely concentrates on studies from USA/EU data, not much data from Indian. In our view, it is important as the phoneme-graphic correspondence is significantly different from English. Further, auditory processing impairment is correlated with VOT from western data. This cannot be directly implied for the same in the Indian population as VOT properties of Indians are very different. So, I feel that Introduction needs more specific to the population under study. Response 1: Thanks for the comment. The issue has been addressed in the response to the fifth comment. Comment 2: Are the results of the TFS-1-test reliable for the age range under study? because the TFS values are poor compare to the literature. From the description in the present study, it is difficult to understand if the results are reliable. Further, there is a published study cited or that available none adopted TFS-1 test many adopted TFS-LF. This needs to be clarified. Response 2: We do agree that the TFS values are poor compare to the literature. We would like to bring to the reviewer’s notice that, the primary objective of the study is to compare the performance between the typically developing children and children with RD. The test was performed under the assumption that the difficulty level would be the same for both groups. Also, participants of both groups were underwent testing after the training with the task. We do agree with the reviewer that TFS-LF is another test to assess the temporal fine structure sensitivity. However, various studies have established that discrimination of harmonic complex and frequency-shifted in-harmonic complex (as in TFS1 test) can be used as a measure of TFS sensitivity. E.g., (Marmel et al., 2015; Moore & Sek, 2009; Moore & Sęk, 2011). Response 3: Incorporated. Page No. 3 (Line no. 2-6) Comment 3: The concurrent vowel identification task looks simple discrimination task, and it is far from auditory stream segregation. The author needs to provide evidence that such a task is considered as auditory stream segregation. Response 3: Various studies(Cheveigné, 1997; Chintanpalli et al., 2016; Settibhaktini et al., 2021; Settibhaktini & Chintanpalli, 2020; Smith et al., 2018) have indicated that F0 guided segregation as a mechanism behind concurrent vowel perception. Hence in the current study, concurrent vowel identification task is used as a measure of concurrent sound segregation. Each vowel acts as an interferer for the other vowel, thereby increasing the perceptual difficulty. For the optimal identification, the target vowel should be segregated from the noise for which the F0 difference is one of the potential cues. Comment 4: Introduction-Para-1: Authors provide the % of RD from the western population. It would be more appropriate if they provide the same from the Indian population. Response 4: Incorporated. Page No. 3 (Line no. 2-6) Comment 5: Introduction-Para-1: Impaired phoneme-grapheme correspondence impairment varies largely with Language. As English is complicated with reference to phoneme-grapheme correspondence, compare to Indian languages. Response 5: The languages vary depending upon the orthographic transparency and consistency. The alphabetic language such as English is less transparent and inconsistent because one grapheme (alphabet) can correspond with many phonemic realizations. In contrast, alphasyllabary languages are more transparent and consistent, because one grapheme (Akshara) corresponds to single-syllable most of the time. To be specific, the primary mapping of phonology in Kannada is at the level of the orthographic syllable (syllabic) but the symbols of the language also embody phoneme markers (hence alphasyllabic). Children with dyslexia in alphasyllabary languages exhibit primary deficits in the acquisition of Akshara knowledge besides phonological awareness deficits at the syllable level. Hence, the basic word decoding is universal across all the languages, where the sounding out requires the conversion of the written symbol (grapheme) with the corresponding linguistic unit (phoneme or syllable), which necessitates both phonological and orthographic processing. Comment 6: Method-TSF-test: Did the authors adopted the procedure developed by Prof. Moore or they used software developed by them. It is not clear from the description. Response 6: The TFS-test developed by Prof. Moore was not used in the current study. However, a similar test was adopted. The procedure used in the current study was similar to the test developed by Prof. Moore, except for the background noise. Pink noise was used to prevent the audibility of combination tone and spectral cues, instead of TEN noise. The correction is incorporated in the revised manuscript."
}
]
},
{
"id": "84193",
"date": "24 May 2021",
"name": "Prashanth Prabhu P",
"expertise": [
"Reviewer Expertise Psychoacoustics",
"Tinnitus and Hyperacusis",
"Auditory neuropathy spectrum disorders",
"central auditory processing disorders"
],
"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 attempted to assess the temporal fine structure and concurrent vowel perception in those with reading disabilities. The article is written well but has the following issues to be addressed:\nThe authors should clarify the difference between dyslexia and reading disability (RD) as the authors use RD throughout the manuscript.\n\nIt is not clear how writing difficulties, cognitive delays, auditory processing disorder was ruled out in the participants. This is important as it can affect the test results.\n\nHow did the authors decide that the participants did not have any gross otologic and neurologic deficits?\n\nWhich test was used to determine the normality of the data?\n\nThe authors carried out repeated measures ANOVA and post hoc comparisons. The results of post-hoc comparisons are missing. The subsequent discussion on the same should be added.\n\nThe authors also report that they carried out ‘Pearson correlation co-efficient to know the association between the performance of TFSI with concurrent vowel identification abilities among RD and TD’. However, the results of the above are completely missing.\n\nThe major content in the last paragraph is a repetition of the results which is not necessary.\n\nDiscussion should be further strengthened on reasons for poor performance and its clinical implications.\n\nLimitations of the study should be addressed.\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": "7497",
"date": "15 Dec 2021",
"name": "Somashekara Haralakatta Shivananjappa",
"role": "Author Response",
"response": "We thank the reviewer for the comments. Following are the responses to the reviewer's comments. Comment 1: The authors should clarify the difference between dyslexia and reading disability (RD) as the authors use RD throughout the manuscript. Response 1: Incorporated in the first paragraph of the introduction. Page No. 3 (Line no. 4-9) Comment 2: It is not clear how writing difficulties, cognitive delays, auditory processing disorder was ruled out in the participants. This is important as it can affect the test results. Response 2: The present study concentrated on children with reading disabilities alone, hence no writing difficulties were not assessed. Children from both groups belong to schools for typically developing children and had age-appropriate language skills according to Linguistic Profile Test (LPT). Since the study aimed to assess auditory processing skills of children with RD in comparison with typically developing children using TFS and concurrent vowel identification, the auditory processing was not separately assessed. Comment 3: How did the authors decide that the participants did not have any gross otologic and neurologic deficits? Response 3: All the children were evaluated for hearing sensitivity using pure tone audiometry. The parental interview was conducted to determine the history of otological diseases and neurological deficits. Comment 4: Which test was used to determine the normality of the data? Response 4: Shapiro-Wilk was used to determine the normality of the data. Comment 5: The authors carried out repeated measures ANOVA and post hoc comparisons. The results of post-hoc comparisons are missing. The subsequent discussion on the same should be added. Response 5: ANOVA with repeated measures revealed a significant main effect of reading ability on CVI scores. Also, the effect of f0 difference was significant. Nevertheless, the interaction between reading ability and F0 difference was not significant. Therefore, the follow-up pair-wise comparison was not performed, as the primary objective of the study was to investigate the effect of reading ability on CVI. However, to comply with the reviewers’ suggestion, we have now performed an independent sample ‘t’ test to assess the effect of reading ability on CVI at each F0 difference condition. The findings are mentioned in the results section. Page No.8 (Line no. 1-5), and Page No. 9 (Line no.13 -23). Comment 6:The authors also report that they carried out ‘Pearson correlation co-efficient to know the association between the performance of TFSI with concurrent vowel identification abilities among RD and TD’. However, the results of the above are completely missing. Response 6: Thanks for pointing out the typological error, and the sentence has been removed from the manuscript. Page No. 6 (Line No. 38-40). Comment 7: The major content in the last paragraph is a repetition of the results which is not necessary Response: Incorporated. Comment 8: Discussion should be further strengthened on reasons for poor performance and its clinical implications. Response 8: Incorporated. Page No. 8 (Line No. 29-34). Comment 9: Limitations of the study should be addressed. Response 9: Incorporated. Page No.8 (Line No. 35-38)"
}
]
},
{
"id": "84199",
"date": "21 Jun 2021",
"name": "Ramesh Kaipa",
"expertise": [
"Reviewer Expertise Speech and Language Intervention"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the current study, the authors have attempted to investigate temporal fine structure in children with reading disability. It is an interesting and timely study but I have some minor comments to improve the rigor of this study.\nI would appreciate it if the authors are able to provide some information on tests that investigate TFS.\n\nIs Reading Acquisition Profile in Kannada a test for reading disability?\n\nWas it not possible for the authors to use a standardized test such as Dyslexia Assessment for Languages in India (DALI) to assess for reading disability instead of using the 2SD approach?\n\nI was curious as to why did the authors use synthesized vowels as stimuli for the vowel identification task over live voice?\n\n5. Although the authors mention that they intended to correlate the outcomes of the vowel identification task and the TFS1, I failed to notice the results of the correlation.\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": "7498",
"date": "15 Dec 2021",
"name": "Somashekara Haralakatta Shivananjappa",
"role": "Author Response",
"response": "We thank the reviewer for the comments Comment 1: I would appreciate it if the authors are able to provide some information on tests that investigate TFS. Response 1: Thank you. The tests for measuring TFS has been mentioned in the introduction section. Due to the word limit, the detailed description of each test has not been mentioned. However, the relevant literature has been cited for the readers to explore further. Page No. 4 (Line no. 14-16) Comment 2: Is Reading Acquisition Profile in Kannada a test for reading disability? Response 2: Though the Reading Acquisition Profile in Kannada is not a test to identify reading disability, it is a content validated reading assessment battery to profile the language skills, metaphonologogical skills, reading and writing skills, reading comprehension tests, and listening comprehension that are key determiners of reading disability in children. The children’s performance on RAP-K supplements the identification of reading disability. It is developed for children learning to read Kannada, following the curriculum affiliated to the Karnataka state board, which is similar to the present study population. Hence, considering the 2SD approach was found to be feasible. Comment 3: Was it not possible for the authors to use a standardized test such as Dyslexia Assessment for Languages in India (DALI) to assess for reading disability instead of using the 2SD approach? Response 3: Yes. DALI could have also been used. However, DALI was not available in the center at the time of the study. Comment 4: I was curious as to why did the authors use synthesized vowels as stimuli for the vowel identification task over live voice? Response 4: In the current study synthesized vowels were preferred over the naturally produced vowels to exert better control over the pitch contours and formants. Comment 5: Although the authors mention that they intended to correlate the outcomes of the vowel identification task and the TFS1, I failed to notice the results of the correlation. Response 5: Thanks for pointing out the typological error, and the sentence has been removed from the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1271
|
https://f1000research.com/articles/10-1285/v1
|
15 Dec 21
|
{
"type": "Research Article",
"title": "Availability and use of technology for e-learning: to what extent do these impact Bangladeshi university students? A cross-sectional study",
"authors": [
"Md. Kamrul Hasan",
"Tajrin Tahrin Tonmon",
"Humayun Kabir",
"Sumaya Binte Masud",
"Md. Abeed Hasan",
"Bikash Das",
"Monira Akter",
"Mohammad Delwer Hossain Hawlader",
"Dipak Kumar Mitra",
"Tajrin Tahrin Tonmon",
"Sumaya Binte Masud",
"Md. Abeed Hasan",
"Bikash Das",
"Monira Akter",
"Mohammad Delwer Hossain Hawlader",
"Dipak Kumar Mitra"
],
"abstract": "Background: E-learning is making education globally and conveniently attainable with the deliverance of advanced technology. However, this mode of academia is still not commonly practiced locally. Thus, the study aimed to investigate technological availability, usability, and association to university students' perceived stress due to e-learning curriculum. Methods: A cross-sectional study commenced among Bangladeshi university students enrolled in the e-learning curriculum. A total of 1162 university students were included. The main explanatory variables were related to the availability of technology and the use of technology. The outcome variable was perceived e-learning stress. In statistical analysis, p-value < 0.05 was considered statistically significant with a 95% confidence interval. Results: In this study, lack of technological availability and usability were associated with higher level of perceived e-learning stress. Being female, living in rural areas, and outside of Dhaka division were found the associated factors in the lack of technological availability and usability. Conclusions: A significant association between the availability and usability of technology with perceived e-learning stress was observed. Thus, measures should be taken to initialize e-learning adaptivity by increasing technological growth across the nation, considering educational preparedness for future catastrophes.",
"keywords": [
"E-learning",
"availability of technology",
"use of technology",
"readiness",
"stress"
],
"content": "1. Introduction\n\nWith the widespread of coronavirus disease (COVID-19), measures are being taken to control the spreading while not hampering the success of academia. Educators and their students have encountered the e-learning process globally (Bao, 2020). The vast gain in the influence of technology since the 1990s has been impacting the education system, amongst which e-learning is being adopted globally (Barrot, Llenares, & del Rosario, 2021). Accordingly, the ‘digitalization’ process in education has been launched attached with a series of virtual management and digital competencies (Purnama, Ulfah, Machali, Wibowo, & Narmaditya, 2021). Keeping pace with that, the effectiveness of e-learning is dependent on the optimism towards it and having fluency in technologies (Çevik & Bakioğlu, 2021). Computer competency, especially internet usability, has powered a prodigious growth in e-learning, where institutions have integrated virtual classrooms into their curriculum to continue education (Almossa, 2021; Mgutshini, 2013). This adoption has provided opportunities for students to enhance their competencies (Churiyah, Sholikhan, Filianti, & Sakdiyyah, 2020; Siron, Wibowo, & Narmaditya, 2020) and attributed it to a requirement of developing digital literacy skills (Phuapan, Viriyavejakul, & Pimdee, 2016; Purnama et al., 2021).\n\nRecently, various web-based free accessed platforms have been used to continue education (Ali, Ramay, & Shahzad, 2011; Keskin & Yurdugül, 2020; Salta, Paschalidou, Tsetseri, & Koulougliotis, 2021). This virtual learning-enabled communication is convenient, especially for introverts (Salta et al., 2021; Walker, Rossi, Anastasi, Gray-Ganter, & Tennent, 2016). Nevertheless, obstacles remain in technological dilemmas, poor internet providers and limited adaptability, creating hurdles for the students (Al-Amin et al., 2021; Katz, Jordan, & Ognyanova, 2021; Shaukat, Niazi, Qazi, & Basit, 2021). Studies have shown that 70% of online students have faced technological errors or computer issues in this web-based pedagogical system (Al-Amin et al., 2021; Yan et al., 2021). Hence, users’ self-ability in e-learning was noted to affect the learning experience (Prifti, 2020; Sarwar et al., 2020). Alqurashi (2016) investigated computer and internet usability and showed a satisfactory experience was positively and significantly associated with e-learning exposure in several studies (Alqurashi, 2016; Daniels, Goegan, & Parker, 2021; Liu & Larose, 2008; Saif Almuraqab, 2020).\n\nAdequate technological support was needed for the students to explore lesson materials. Several research assessed that students were getting anxious while acquiring lessons due to technological issues (Ali et al., 2011; Alzahrani & Seth, 2021; Çevik & Bakioğlu, 2021; Maheshwari, 2021). Whereas, with adequate technological support, students retrieved classes from anywhere at any time (Al-Azzam, Elsalem, & Gombedza, 2020; Kumar, Kumar, & Ting, 2021). The e-learning experience in this context varied on factors like gender, residence, region and minority groups; (Abuhassna et al., 2020; Alqurashi, 2019; Alyoussef, 2021; Shahzad, Hassan, Aremu, Hussain, & Lodhi, 2021). Hence, increasing the dropout rates (Cromley & Kunze, 2021; Yang, Peng, Wong, & Chong, 2021).\n\nBesides, the transition from traditional to e-learning has created numerous issues for educators and university students of various disciplines (Giray, 2021; Hsu, Wang, & Levesque-Bristol, 2019). As the curriculum was not designed for online learning (Dong et al., 2020; Misirli & Ergulec, 2021), it was reported as complicated to bring a change into it. Additionally, unequipped digital resources accelerated the complication for the learners in remote areas (Rahiem, 2021). Over time, unequal access and distribution of adequate resources have been established due to differences in backgrounds (Yu, Zhang, & Zou, 2021). Again, the various home environments of the students do not allow an equal environment for all, which is opposed by the traditional education environment (Kumar et al., 2021). Therefore, the call for equity is a matter of concern, and the issues of technological inequalities and digital disparities are foremost to be disrupted (Klümper et al., 2016). The United Nations Educational, Scientific and Cultural Organization-International Institute for Educational Planning has already emphasized that maintaining equity is a great challenge with the transition to learning remotely (Istenič, 2021).\n\nWhen researched further, perceived stress of e-learning was also found as one of the outcomes of the e-learning curriculum (Alqurashi, 2016). With the deadly COVID-19 condition, young students are victims of accelerated stress, anxiety, and depression development, hindering their growth in education (Shaukat et al., 2021; Vayre & Vonthron, 2019). Studies have shown that e-learning during this pandemic has created psychological and intellectual gaps among students because of resource constraints (Al-Balas et al., 2020; Yang, Quadir, Chen, & Miao, 2016; Yang et al., 2021). Students worldwide were already worried about the impact of the virus (Wang & Zhao, 2020; Wang et al., 2020), and the pedagogical changes found increased stress level among females particularly (Almossa, 2021).\n\nAccording to the United Nations, the disruption due to COVID-19 in the education sector impacted more than 72% of the students in the world (Kumar et al., 2021; Sarwar et al., 2020). To overcome the disruption, internet, audio and video lectures, television and radio broadcasts, and available CDs have been used as lessons for the students in Pakistan. Kapasia et al. (2020) examined in India that students who belonged to remote regions and underprivileged residences were confronted with numerous issues related to mental health, network connectivity, and unsupportive home conditions (Kapasia et al., 2020). Meanwhile, Indonesian students also complained about technological interference, costly internet, lack of digital skills, and difficulties accessing learning materials (Rahiem, 2020).\n\nMeanwhile, in Bangladesh, universities started conducting online education in accordance with the declaration of the Ministry of Education. However, studies found disinterest among the students due to unpreparedness and lack of proper technological services (Emon, Alif, & Islam, 2020). In contrast, a study found that 70% of the attendees of online classes belonged to private universities (Ramij & Sultana, 2020) (Islam et al., 2020). The Bangladeshi university students are willing to learn online, although the affordability of technological tools' has hindered their willingness to continue (Al-Amin et al., 2021). Though online classes are not new for neighboring countries, keeping up with online classes extensively in developing countries like Bangladesh is not free of problems (Shaukat et al., 2021). However, sufficient studies have not been conducted nationwide scrutinizing these issues so far.\n\nTherefore, this study aimed to observe the prevalence of technological availability and diversity of using technology to derive usability among university students. In addition, the study investigated students’ technological availability and usability association to perceived stress due to e-learning. This study may help policymakers, aiding them in coming up with unique solutions to improve the quality and equity of education.\n\n\n2. Methodology\n\nIn Bangladesh, a cross-sectional study was conducted between December 26, 2020, and January 11, 2021. The inclusion criteria included: (a) enrolled Bangladeshi university students, (b) age at least 18 years, (c) enrolled e-learning curriculum for 30 days during the pandemic, and (d) participated by giving online consent.\n\nDue to the COVID-19 pandemic, face-to-face data collection was prohibited. Therefore, data for this study were collected online (using “Google Forms”), followed by convenience and snowball sampling methods when schools were closed due to COVID-19 pandemic. The questionnaire link was posted in university students' social media groups (Facebook, Messenger, and WhatsApp). After screening all collected data and dropping data with missing responses, 1162 completed responses were included in the final analysis.\n\nThe study’s explanatory variables were e-learning related information such as (a) availability of technology (6 items) included hardware and software facilities, internet speed and stability, computer access and internet connectivity for the technology availability subdomain, and (b) use of technology (11 items) included information via the internet, e-mail communication, office software, programming software, messaging apps, web tools, file hosting services, learning management systems, online forums, internet connectivity via mobile technologies. This measure was adopted by an e-learning readiness questionnaire (Kabir et al., 2021; Soydal, Alir, & Ünal, 2011; Ünal, Alir, & Soydal, 2014). The responses were in a five-point Likert scale of 1 for “strongly disagree,” and 5 for “strongly agree.” The availability of technology score ranges from 6 to 30, and the score of use of technology ranges from 11 to 55. However, the responses can be categorized into (1) sub-optimum and (2) optimum. Identification of optimum response was defined as the mean score of the item is 3.40 or greater (Akaslan & Law, 2011; Soydal et al., 2011; Ünal et al., 2014).\n\nThe outcome of e-learning, perceived e-learning stress was measured using a self-reported 14 items’ perceived stress scale (PSS). The total scores can range from 0 to 56. However, the PSS is restricted to measure perceived stress in the last month. We used PSS to measure the e-learning related stress by making a slight phrasal modification (Lazarevic & Bentz, 2020; Program, 1983). Without changing the actual meaning of PSS, the modification was performed by adding the term “of e-learning” with each item to adjust the context to e-learning by following Lazarevic et al. (Cronbach’s alpha = 0.83) (Lazarevic & Bentz, 2020). In PSS, an item “In the last month, how often have you found that you could not cope with all the things that you had to do?” After the modification, it looked like, “In the last month of e-learning, how often have you found that you could not cope with all the things that you had to do?” The response is in a five-point Likert scale of 0 for “Never” and 4 for “Very often”. To calculate total scores, reversed the scores (e.g., 0 = 4, 1 = 3 … & 4 = 0) of four positively response items (items 4, 5, 7, & 8) and then have to sum all the 14 items. For PSS, Cronbach’s alpha was found 0.86, which indicated good internal consistency.\n\nAll analyses were carried out using statistical software packages Stata version 16 (StataCorp, Texas, US) (RRID: SCR 012763). Initially, descriptive and inferential statistics such as central tendency, chi-squared (χ2) tests, and t-test were carried out. The chi-square test was performed to examine the associations of technology availability categories and technology usability categories with different sample characteristics by gender, residence, and division. The association of availability and usability of technology categories with perceived stress score was examined using the t-test. Subsequently, the Pearson correlation coefficient test was used for examining the correlation of the sum score of availability and use of technology and PSS score. All statistical tests were two-sided, and a p-value < 0.05 was considered statistically significant for all the tests performed at 95% confidence interval.\n\nAll the procedures were conducted following the institution's review board (IRB) of North South University, Bangladesh (Memo no. 2021/OR-NSU/IRB/0601). The ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards were followed wherever applicable. Electronic consent was attached for all the participants involved in the study, and the respondents who were willing to participate were only considered as respondents. However, the study's nature, purpose, and objective were clearly stated, along with the declaration of confidentiality and anonymity on the first page of the questionnaire.\n\n\n3. Results\n\nThe distribution of technological availability related variables are presented by gender, residence, and division are presented in Table 1. Compared to males, females were at more sub-optimum level with hardware facilities (55.64%; p = 0.004), software facilities (57.34%; p < 0.001), access to a computer whenever needed (56.83%; p = 0.001) and internet connectivity whenever needed (55.66%; p = 0.01). The rural students were at a sub-optimum level with hardware facilities (41.04%; p = 0.004), software facilities (41.60%; p = 0.002), good internet speed (41.94%; p < 0.001), satisfactory internet stability (41.76%; p < 0.001), access to a computer whenever needed (46.25%; p < 0.001) and internet connectivity whenever needed (45.61%; p < 0.001) compared to urban students. Along with this, the students outside the Dhaka division were at more non-optimized hardware facilities (32.95%; p = 0.002), non-optimized software facilities (33.74%; p < 0.001), more sub-optimal access to high internet speeds (33.42%; p < 0.001), higher levels of sub-optimal satisfaction with stability of the internet connection (33.38%; p < 0.001), higher levels of sub-optimal access to a computer whenever needed (36.69%; p < 0.001) and more sub-optimum connectivity to the internet whenever needed (35.89%; p < 0.001) compared to the students of Dhaka division.\n\nIn Table 2, distribution of technological usability related variables by gender, residence, and division are presented. The females were at more sub-optimum level of office software usability (59.72%, p < 0.001), programming language software usability (55.06%, p = 0.001), web 2.0 tools usability (55.19%, p < 0.001), file hosting services usability (56.17%, p = 0.005) and learning management systems usability (55.03%, p < 0.001). Alongside, the rural students were at more sub-optimum level of internet usability (45.14%, p < 0.001), e-mail communication (42.56%, p = 0.001), office software usability (46.64%, p < 0.001), social network usability (45.69%, p = 0.01), instant messaging usability (42.58%, p < 0.001), Web 2.0 tools usability (39.57%, p = 0.02), file hosting services usability (44.00%, p < 0.001) and learning management systems usability (39.26%, p = 0.04). Suboptimum usability of technology was found to be higher among the students outside the Dhaka division for internet usability (38.52%, p < 0.001), e-mail communication (34.33%, p = 0.001), office software usability (34.98%, p < 0.001), programming language software usability (31.76%, p = 0.008), social network usability (36.04%, p = 0.03), instant messaging usability (32.14%, p = 0.046), file hosting services usability (34.50%, p < 0.001), learning management systems usability (31.54%, p = 0.008), online forum usability (33.86%, p = 0.002) and mobile technologies usability (40.48%, p < 0.001).\n\nThe association between the availability of technology and perceived e-learning stress is presented in Table 1. The mean scores of e-learning stress was significantly higher for a sub-optimum level of hardware facilities (p < 0.001), software facilities (p < 0.001), internet speed (p < 0.001), internet stability (p < 0.001), access to computer when needed (p < 0.001), and connectivity to internet whenever needed (p < 0.001).\n\nAssociation between use of technology and perceived e-learning stress are presented in Table 2. The higher mean scores of e-learning stress were observed among the sub-optimum categories for internet usability (p < 0.001), e-mail communication (p < 0.001), office software usability (p < 0.001), instant messaging usability (p = 0.003), file hosting services usability (p < 0.001), learning management systems (p = 0.003), and online forum usability (p = 0.012).\n\nThe score of availability of technology, use of technology, and PSS was significantly correlated (Table 3). The result showed that the availability of technology was positively correlated with the technology (p < 0.001). On the other hand, the availability of technology was negatively correlated with the PSS score (p < 0.001).\n\n\n4. Discussion\n\nThis study investigated the prevalence of technology availability and usability among university students. All the factors defining e-learning readiness in the context of technological availability and usability are significantly associated with perceived e-learning stress. To the best of the authors' knowledge, no other studies in developing countries like Bangladesh accessed the prevalence of students' technological availability and uasability.\n\nIn this study, sub-optimum hardware and software facilities were found to be significantly associated with the students' perceived stress score. The prevalence of these facilities was sub-optimum, especially among females, rural students, and students outside Dhaka. In an Indonesian study, Churiyah et al. (2020), observed that the lack of electronic devices and technological infrastructure in institutions had hampered the students' educational growth. Conversely, Alghamdi et al. (2020), identified that American students had performed better in online learning structure than the traditional settings with the help of necessary technological support, e.g., video and audio lectures, accessible communication etc. From our country’s perspective, the availability of hardware and software devices is comparatively prominent in Dhaka. Students residing in rural settings tend to be less facilitated regarding technical support because of financial and lack of digitalization contexts. Bangladesh is being digitalized adequately recently, which is also available within a homogenous stratum, e.g., citizens of Dhaka. As availability concerns were being addressed, the priority put the males in front of the queue, cooperating with the findings of our study. With the concerning availability of device facilities, stress is a common outcome for university students whose education is still entirely dependent on e-learning.\n\nIt was also found that on dissatisfactory level, sub-optimal internet speed and internet stability were two other factors found associated with females, rurality, and residency outside Dhaka when stratified. It, too, had a significant effect on the students’ stress levels. Barrot et al. (2021), stated that among the Philippine's students, the technological barrier at home, poor internet connectivity, and stability hindered their education and caused a significant challenge. In Bangladesh, internet speed and stability rely on the connection providers, and due to the sudden pandemic situation and lockdown at short notice, the internet usage and human dependency on it raised, which might have increased the pressure for the internet connection providers. Ali et al. (2011), in Pakistan, and Almossa et al. (2021) in Saudi Arabia showed students’ dissatisfaction due to issues with the internet. Moreover, it might be a profound reason for students’ e-learning stress.\n\nAlongside this, sub-optimal access to computers and internet connectivity whenever needed was also prevalent when it came to students' needs. These factors affected the stress of students’ e-learning exposure. Bangladeshi academia was always entirely focused on the in-person educational structure where students were never habituated with technological dependency. With the outbreak of COVID-19, most students were compelled to shift online learning structure to avoid their study gap. This sudden shift could not prepare the students equally from gender, rurality, and non-centralized perspectives. Therefore, females being less exposed to the internet and computer systems, specifically when it comes to rural areas, are often disadvantaged. The students in the periphery do not get computer and internet connections available whenever needed. This could be a plausible explanation for being significantly associated with stress. Several studies were found in agreement with our findings (Barrot et al., 2021; Keskin & Yurdugül, 2020; Purnama et al., 2021). On the other hand, Purnama et al. (2021), assessed the risk of internet misusing and cyberbullying increasing along with the free access of computers and the internet.\n\nLike availability, the usability of technology was also observed to be significantly sub-optimum among females, rural and students outside Dhaka. It was found to affect the stress score of students significantly. Numerous studies found students and teachers were struggling when it came to self-efficacy of internet use. Students have seen issues due to their lack of knowledge on internet usage in an academic context and teachers' struggling due to lack of internet exposure (Bao, 2020; Churiyah et al., 2020; Siron et al., 2020). From a general perspective, people in Bangladesh are used to internet usage, but mainly for social media purposes. When stratified by gender, Bangladeshi females were found less technological usability, which can explain that they are primarily occupied doing chores. A similar scenario was found outside of Dhaka, where students may optimize their time with outdoor activities. In rural settings, students maintain routine lifestyle that is more scheduled with in-person interactions. These might be reasons beneath the observed prevalence, hence, affecting students’ stress levels.\n\nFemale, rural, and outside Dhaka were seen to have sub-optimum prevalence when communicating via e-mail. This factor not only was prevalent but also accelerated the stress among the students. E-mail communication is not a common way of interacting for this generation in Bangladesh. Social networking systems have changed their communication habits and made them more informal. Bangladeshi students are more comfortable making a phone call or sending a text in or messaging on Facebook, WhatsApp etc. However, regarding the rural perspective, students and teachers prefer to respond via mobile call or direct communications rather than e-mail. Moreover, Bangladeshi females and peripheric students are less technologically adept due to the behavioral and cultural norms practiced for a long time. Studies supporting our findings showed the importance of online communication in this digital era (Alghamdi et al., 2020; Walker et al., 2016).\n\nA significant difference in sub-optimal means was found with office software usability compared to the optimal usability. Many Turkish, Indonesian, and Jordanian studies explored that expertise and skills in office software usage could benefit students of all levels (Çevik & Bakioğlu, 2021; Siron et al., 2020). From an overall perspective, students in our country are less used to the usability of technology such as Microsoft office. The prominent structure of regular face-to-face classes never required them to be. Thus, the complete curriculum shift depending on software usage could be the reason for such findings, causing extreme stress levels in the students.\n\nIn this study, instant messaging, file hosting services, learning management systems, and online forum usability were some of the signs found as associated factors. These affected the students’ stress levels with a higher difference of means compared to optimality. The reason could be the never-needed functionality for rural students in online forms of communication. As for the female and non-centralized students, women here are less keen to explore the numerous technological mediums and devices except for the most common platforms. Studies from various continents found similar outcomes and concluded with its importance in developing a solid e-learning system (Purnama et al., 2021). Here in Bangladesh, another general reason could be the expense regarding the usage, looking at most university students' cultural and socioeconomic backgrounds.\n\n\n5. Limitations and strengths\n\nDue to lockdown, the online snowball sampling technique was applied that is one of the limitations of our study, compromising the randomization of students. Recall bias of the respondent could not be excluded due to the self-reported online questionnaire approach. A tool to collect qualitative and quantitative data could bring up some narratives of the students’ experiences for a deeper understanding.\n\nThis study enrolled students with a moderate sample size to be addressed as a representative study keeping in mind the lockdown situation of university students. This study also considered the various factors associated with the technological barriers that the e-learning community is facing. It may help policymakers developing the technological ground for academia to avoid educational hindrances due to any emerging situation, similar to the COVID-19 pandemic. For further research recommendation, a more rigorous analytical study on the subject matter could be informative.\n\n\n6. Conclusion\n\nThis study assessed the technological stands of the university students' usability and technical support availability. The study found that lack of technological stands affects the stress level of the students enrolled in an online curriculum. However, the findings strongly suggest the relevant authorities take steps to revitalize the curriculum of e-learning to be adaptive to technology. Such awareness steps would facilitate the students' technical knowledge development, which is essential for building digital Bangladesh and accelerating digital literacy. Hence, preparing the academicians always to be more ready to tackle hurdles such as pandemics and transform the curriculum into e-learning from traditional rapidly whenever needed.\n\n\n7. Recommendations\n\nAssessing the prevalence of sub-optimum and optimum technological availability and usability among university students and their association with perceived e-learning stress may highlight the education system's infrastructure. Insights from identifying the effect of students’ technological condition and supporting initiatives to reduce their stress level can be used to derive the corrective action(s) that needs to be assessed for building digital Bangladesh.\n\n\nData availability\n\nZenodo: Availability and use of technology for e-learning in Bangladesh https://doi.org/10.5281/zenodo.5748586.\n\nThis project contains the following underlying data:\n\n• Data.xls (raw data from questionnaires)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nConsent\n\nInformed electronic consent was obtained for all the participants involved in the study.",
"appendix": "Acknowledgments\n\nWe would like to accolade all the research assistants of the project who assisted in data collection.\n\n\nReferences\n\nAbuhassna H, Al-Rahmi WM, Yahya N, et al.: Development of a new model on utilizing online learning platforms to improve students’ academic achievements and satisfaction. Int. J. Educ. Technol. High. Educ. 2020; 17(1): 1–23. Publisher Full Text\n\nAkaslan D, Law ELC: Measuring student e-learning readiness: a case about the subject of electricity in higher education institutions in Turkey. Lecture Notes in Computer Science (Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 7048 LNCS. 2011; 209–218. Publisher Full Text\n\nAl-Amin M, Al Zubayer A , Deb B, et al.: Status of tertiary level online class in Bangladesh: students’ response on preparedness, participation and classroom activities. Heliyon. 2021; 7(1): e05943. 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PubMed Abstract | Publisher Full Text\n\nRahiem MDH: Technological barriers and challenges in the use of ICT during the COVID-19 emergency remote learning. Univ. J. Educ. Res. 2020; 8(11B): 6124–6133. Publisher Full Text\n\nRahiem MDH: Remaining motivated despite the limitations: university students’ learning propensity during the COVID-19 pandemic. Child Youth Serv. Rev. 2021; 120: 105802. PubMed Abstract | Publisher Full Text\n\nRamij MG, Sultana A: Preparedness of online classes in developing countries amid COVID-19 outbreak: a perspective from Bangladesh. SSRN Electron. J. 2020. Publisher Full Text\n\nSaif Almuraqab NA: Shall universities at the UAE continue distance learning after the CoviD-19 pandemic? revealing students’ perspective. Int. J. Adv. Res. Eng. Technol. 2020; 11(5): 226–233. Publisher Full Text\n\nSalta K, Paschalidou K, Tsetseri M, et al.: Shift from a traditional to a distance learning environment during the COVID-19 pandemic: university students’ engagement and interactions. Sci. Educ. 2021; 1–30. PubMed Abstract | Publisher Full Text\n\nSarwar H, Akhtar H, Naeem MM, et al.: Self-reported effectiveness of e-learning classes during COVID-19 pandemic: a nation-wide survey of Pakistani undergraduate dentistry students. Eur. J. Dent. 2020; 14: S34–S43. PubMed Abstract | Publisher Full Text\n\nShahzad A, Hassan R, Aremu AY, et al.: Effects of COVID-19 in e-learning on higher education institution students: the group comparison between male and female. Qual. Quant. 2021; 55(3): 805–826. Publisher Full Text\n\nShaukat MZ, Niazi AAK, Qazi TF, et al.: Analyzing the underlying structure of online teaching during the COVID-19 pandemic period: an empirical investigation of issues of students. Front. Psychol. 2021; 12(April): 1–12. PubMed Abstract | Publisher Full Text\n\nSiron Y, Wibowo A, Narmaditya BS: Factors affecting the adoption of e-learning in indonesia: lesson from covid-19. J. Technol. Sci. Educ. 2020; 10(2): 282–295. Publisher Full Text\n\nSoydal R, Alir G, Ünal Y: Are Turkish universities ready for e-learning: a case of Hacettepe University faculty of letters. Inf. Serv. Use. 2011; 31(3–4): 281–291. IOS Press. Publisher Full Text\n\nÜnal Y, Alir G, Soydal İ: Students readiness for e-learning: an assessment on Hacettepe university department of information management. Commun. Comput. Inf. Sci. 2014; 423: 137–147. Publisher Full Text\n\nVayre E, Vonthron AM: Relational and psychological factors affecting exam participation and student achievement in online college courses. Internet High. Educ. 2019; 43(November): 0–1. Publisher Full Text\n\nWalker S, Rossi D, Anastasi J, et al.: Indicators of undergraduate nursing students’ satisfaction with their learning journey: an integrative review. Nurse Educ. 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}
|
[
{
"id": "124018",
"date": "15 Mar 2022",
"name": "Saeed Anwar",
"expertise": [],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research by the authors is an important inquiry into the crucial issue of e-learning imposed by the new normal and the associated challenges in an LMIC (quite under-researched in these contexts).\n\nThe authors have planned, managed and written the research very well. Source data is available for almost all the variables of the study. Descriptive and inferential statistics have been applied and related appreciably. The limitations and strengths have been narrated reasonably well, though they might have been even better communicated in user friendly terms by disaggregating them under separate subtitles of ‘LIMITATIONS’ and ‘STRENGTHS’, rather than binding them under one subtitle.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "129294",
"date": "19 Apr 2022",
"name": "Enric Serradell-López",
"expertise": [
"Reviewer Expertise E-learning",
"Management",
"Business games",
"Strategy"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research developed by the authors is focused on one of the hot topics of how the Covid-19 pandemic affects students. They propose the concept of perceived e-learning stress as an attempt to measure the influence of the pandemic on students. As all the indicators are based on perceptions, it is not easy to generalize, but the conclusions obtained are interesting due to the fact that more than one thousand students answered the questionnaire. The data collection is also interesting as they used social networks. The statistical analysis and its interpretation is correct; however, more statistical analysis could be developed, for example cluster or factorial analysis. The underlying data is available so I'd like to congratulate the authors for that. The conclusions are correct and follow the logical of the article. When we talk about e-learning it should be normal to detect the technology needs of the students. The recommendations should be followed by policymakers who must provide sufficient resources to public universities.\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": "134980",
"date": "20 Apr 2022",
"name": "Shaher H Hamaideh",
"expertise": [
"Reviewer Expertise Mental health nursing"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper addressed an important issue about the availability and use of technology for e-learning among university students. This has become an important issue globally due to the pandemic. The authors present the topic appropriately with a good flow, and used appropriate and adequate references and citations. Most of the references are relatively up to date and specifically address the issue of e-learning among university students especially in the period of COVID-19. However, the introduction is a little bit long. The authors may shorten it and combine similar points where applicable.\n\nUsing a cross-sectional design to collect data online (using Google forms) is appropriate for the purpose of this study. The data was analyzed and interpreted in the text appropriately. However, the tables are too crowded which makes it difficult for the readers to follow. The conclusions drawn from the study were adequately supported by the results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1285
|
https://f1000research.com/articles/10-1283/v1
|
15 Dec 21
|
{
"type": "Case Report",
"title": "Case Report: Transorbital approach for the management of an orbito-temporal penetrating brain injury (skull base region) secondary to wooden spikes",
"authors": [
"Tedy Apriawan",
"Abdul Hafid Bajamal",
"Ditto Darlan",
"Yusriandi Ramadhan",
"Abdul Hafid Bajamal",
"Ditto Darlan",
"Yusriandi Ramadhan"
],
"abstract": "Background and importance: Transorbital penetrating brain injury (PBI) due to a non-projectile foreign body is rare. It can lead to life-threatening severe neurovascular damage. Surgery is the primary treatment choice; however, there are a number of approaches that can be considered based on the patient's condition in terms of foreign body location and state of the patient. Clinical presentation: An 18-year-old male carpenter was hit by a log and sustained transorbital PBI while cutting wood with a machine. Computed tomography (CT) scan showed a wooden spike that was approximately 11 cm from the left medial orbital to the superior part of the posterolateral of the petrous bone, crossing the right side at the base of the skull. CT angiography (CTA), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) revealed no internal carotid artery (ICA) and cavernous sinus lesions, respectively. We had a 3D-printed model for preoperative planning, and surgery was performed using a transorbital approach to extract the wood 14 days after the accident. The impacted wood was removed without any complications. Conclusion: There are many surgical approaches for transorbital PBI. We decided to perform the transorbital approach because it is perpendicular to the entry zone. Surgeons should consistently perform minimally invasive procedures based on the clinical and radiological findings.",
"keywords": [
"penetrating brain injury",
"PBI surgical management",
"transorbital approach wooden foreign body"
],
"content": "Background and importance\n\nTransorbital penetrating brain injury (PBI) secondary to a non-projectile foreign body is rare and potentially life-threatening. The orbital wall is thin; therefore, access to the cranial cavity through this region can be swift. It can cause severe damage to the eye, optic nerves, brain parenchyma, and neurovascular structures.1 Prevalence studies have reported that transorbital PBI accounts for 45% and 24% of all traumatic brain injury in children and adults, respectively, and accounts for 0.04% of all traumatic brain injury and 4.5% of all orbital pathologies.2,3\n\nTransorbital PBI at the skull base region can cause severe neurovascular damage. Vital structures, such as cranial nerves, arteries, and the cavernous sinus, are of particular concern during preoperative planning for surgery in patients with transorbital PBI in the skull base region.4 Immediate complications (that can occur within a week of injury) include haemorrhage, vascular damage (such as carotid-cavernous fistula [CCF], traumatic aneurysm, and intravascular thrombosis), ischemic brain injury, brain oedema, and cerebral contusion.5 Delayed complications (that can occur after more than a week of injury) include infections (meningitis, encephalitis, and orbital cellulitis), foreign body migration, hydrocephalus, and cerebrospinal fluid (CSF) leakage.5 Therefore, it is essential to understand the mechanism of injury, reconstruction of preoperative planning surgery, and postoperative care.4 The timing of surgery also needs to be considered in patients with a wooden transorbital PBI, especially when it involves a rough wooden surface, as it can cause more severe tissue damage.4 Adequate debridement, administration of antibiotics, and anti-seizure prophylaxis are also required to achieve a satisfactory outcome.6\n\nSurgery is the primary treatment for most cases of transorbital PBI. Available approaches include the transorbital approach, right or left frontal craniotomy applying the subfrontal approach, right or left frontotemporal craniotomy, bifrontal craniotomy using the anterior interhemispheric approach, lobectomy, and the percutaneous lumbar intrathecal approach.7–12 In our case, we considered using the transorbital approach in view of the clinical and radiological features that are associated with such cases of wooden transorbital PBI.\n\n\nClinical presentation\n\nAn 18-year-old male carpenter sustained a wooden PBI at two locations—the right frontoparietal and left orbito-temporal areas, and the base of the skull—while cutting wood with a machine. The wood in the frontoparietal area was extracted, and bone decompression along with evisceration of his left eye were performed six hours after the incident at the district general hospital. Afterwards, the patient was referred to our hospital for further management. He complained of pain and loss of sight in the left eye. He had a Glasgow Coma Scale (GCS) score E4V5M6, trigeminal nerve palsy (V2 and V3), facial nerve palsy of the peripheral type (House Brackmenn grade IV) and left-sided hemiparesis. There was no sign of CSF leakage.\n\nLaboratory examinations revealed leucocytosis and increased C-reactive protein (CRP) and procalcitonin levels. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and a 3D-printed model were used preoperatively to plan for surgery (Figure 1). There were no lesions in the internal carotid artery, cavernous sinus, and transverse sinuses (Figure 2). We surgically extracted the wood 14 days after the accident. Empirical antibiotics were administered for six weeks while awaiting definitive antibiotic treatment based on microbiological and antibiotic susceptibility tests. Phenytoin was administered for a week after the accident for post-traumatic seizure prophylaxis.\n\n(A) The wood is seen to extend from the left medial orbital region, ethmoid sinus, across the contralateral sphenoid sinus, and reach the superior part of the posterolateral surface of the petrous bone before crossing to the right side. (B) Another piece of wood that extends from the right frontal to the right parietal region (about 10 cm long) is also observed. (D) and (E) show bone window segments. (C) and (F) T1-weighted contrast magnetic resonance imaging (MRI) using gadolinium shows that the foreign body had formed a fibrous capsule.\n\n(A), (B), and (C) computed tomography (CT) angiography and reconstruction of the cerebral arteries shows no rupture in the internal carotid artery (ICA). (D) magnetic resonance angiography (MRA) reveals narrowing of the right ICA that is compressed by the one of the pieces of wood. (E) magnetic resonance venography (MRV) shows no lesion in the cavernous sinus.\n\n\nSurgical procedure\n\n\n\n\nPostoperative follow-up\n\nPostoperative CT scan evaluation revealed gross total extraction without any haemorrhagic lesion along with a GCS of E4V5M6 (Figure 4). The patient was discharged six weeks after the pieces of wood were extracted, and no apparent clinical complications and abnormal infectious parameters (leucocyte, CRP, and procalcitonin) were found. Six months postoperatively, there was no feature of trigeminal nor facial palsy. The patient could return to his usual activities, and a customized ocular prosthesis was made for his left eye.\n\n\nDiscussion\n\nThe goals of surgery in cases of wooden transorbital PBI include: (1) debridement of non-vital tissues, considering the extensive damage the wood may have caused; (2) evacuation of hematomas, such as extradural, subdural, and intraparenchymal hematoma; (3) removal of as much bone fragments as possible; (4) retrieval of foreign body fragments (larger fragments should be meticulously sought out, as they tend to migrate); (5) securing of adequate haemostasis; and (6) watertight closure of the dura mater, which usually requires the use of grafts. Turbin anatomical criteria refer to zone 3b (medial canthus) as the area where the orbital area exits at the superior orbital fissure and sphenoid wing.1 The aspects of the central nervous system at risk of damage in that area include the cavernous sinus, temporal lobe, brain stem, or basal cistern.1\n\nIn our case, the patient underwent a two-stage surgery. The first stage of surgery was debridement, surgical extraction of the right frontoparietal wooden object, bone decompression, and left ocular evisceration, which were done six hours after the incident at the district general hospital. The bone flap removed from the injured side was placed on the contralateral subgaleal layer of the injured side. The patient was referred to our hospital because we were more equipped to manage the extraction of the wood from the orbito-temporal part of the base of the skull. In this case we also performed the 3D-printed reconstruction for the surgery plan because 3D-printed model reconstruction can help neurosurgeons for surgical strategies, and it enhances the anatomical visualization of the location and trajectory of the foreign body, which is not completely visible from the outside (Figure 5).13\n\n(A). Tip of the wooden foreign body at the medial orbital wall. (B) and (C) Show that there is no lesion in the internal carotid artery (red) and cavernous sinus (dark blue).\n\nBased on details obtained from CT angiography (CTA), magnetic resonance venography (MRV), MRA, and the 3D-printed reconstruction, no serious neurovascular lesions were seen. Therefore, we decided to perform the second stage of surgery in the orbito-temporal part of the base of the skull base. The patient was positioned supine facing to the right for a transorbital approach, perpendicular to the wooden foreign body’s entry zone. The eyelid was retracted gently, and the flap was sutured using silk 3.0. The conjunctiva was incised horizontally from the medial to the lateral canthus. We performed soft-tissue exploration of the orbit using a Langenbeck retractor until the medial wall of the orbit (ethmoid bone) was visible. When performing soft tissue retraction of the orbit using a Langenbeck retractor, it is essential to pay attention to the presence of an oculocardiac reflex due to stretching of the afferent stretch receptors that are transmitted through the ciliary nerve, Gasserian ganglion, and efferent vagal fibres, which are capable of increasing the parasympathetic tone. This could cause bradycardia in the patient.\n\nAfter exploring the soft tissue of the orbit medially, the superficial tip of the wood was revealed in line with its trajectory. Osteotomy of the interlocking bone around the tip of the wooden foreign body was performed using a Kerrison punch, then the bone around the tip of the wood was meticulously removed. The wooden foreign body was gently extracted, perpendicular to the operator’s view, using a bone rongeur. There was no brisk bleeding from the internal carotid artery nor from the cavernous sinus. Adequate debridement (irrigation for dilution) and haemostasis (using Gelfoam and Surgicel) were achieved after the wood was extracted. The wooden foreign body and the fibrous capsule formed were examined for infection via microbiological culture and antibiotic susceptibility testing. Finally, we sutured the skin in layers and performed tarsorrhaphy. The wood was most probably contaminated; therefore, we debrided any easily accessible impacted bone and other extracranial tissues along the track.\n\nRegarding the timing of surgery, for our patient surgery was performed 14 days after the accident. The purpose of this was to ensure that a consistently thick fibrous capsule had formed over the entire body of the wood. This is a physiological foreign body reaction that protected the brain from the rough surface of the wood. Ibrahim et al., in their experimental study in 2017, reported that the immune response to foreign body implantation began on day 14.14 Mast cells (MC) are mobilized to the site of the wound, where they mature and are activated early in the inflammatory process through chemotactic inflammatory signaling. The activated MC secrete mediators, such as IL-4 and IL-13, attracting macrophages through chemotactic signals. To improve their effectiveness, macrophages fuse to form foreign body massive cells that reside at the tissue interface.15 Foreign-body giant cells are still incapable of digesting large implants but can secrete cytokines that cause fibroblasts to produce a collagen capsule that embraces the foreign body, and this effectively isolates it from surrounding tissue.16 On day 14, the thickest fibrous capsule forms, followed by those on days 60, 90, and 180 (Figure 6).14 Therefore, watchful waiting until day 14 needs to be considered for a hemodynamically stable patient without severe neurovascular complication. Allograft cranioplasty was performed six months after the accident. This was done to reduce the risk of infection.\n\n\nConclusion\n\nMany surgical approaches exist for managing transorbital PBIs. In this case, we decided to perform transorbital approach techniques perpendicular to the entry zone, 14 days after the injury. This enabled us to perform a minimally invasive procedure based on the patient’s clinical and radiological features.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgments\n\nThe authors would like to thank all those who contributed to the process and completion of this report, including all neurosurgery consultant and fellow residents of the Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Surabaya.\n\n\nReferences\n\nTurbin RE, Levin F, Maxwell DN: Recognition of transorbital intracranial injury. Clin. Ophthalmol. (Auckland, N.Z.). 2007; 1(1): 85–89.\n\nLuerssen TG, Klauber MR, Marshall LF: Outcome from head injury related to patient's age. A longitudinal prospective study of adult and pediatric head injury. J. Neurosurg. 1988; 68(3): 409–416. PubMed Abstract | Publisher Full Text\n\nRootman J: Disease of orbit: a multidisciplinary approach. Philadelphia: Lippincot Willian & Wilkins; 1st ed.1988.\n\nXu L, et al.: The Surgical Strategies and Techniques of Transorbital Nonmissile Brain Injury. World Neurosurg. 2020; 144: e856–e865. PubMed Abstract | Publisher Full Text\n\nVakil MT, Singh AK: A review of penetrating brain trauma: epidemiology, pathophysiology, imaging assessment, complications, and treatment. Emerg. Radiol. 2017; 24(3): 301–309. PubMed Abstract | Publisher Full Text\n\nAsadullah, Apriawan T, Bajamal AH, et al.: Management of penetrating brain injury: A case report. Indones. J. Neurosurg. 2020; 3(3): 74–79. Publisher Full Text\n\nSchreckinger M, et al.: Transorbital penetrating injury: case series, review of the literature, and proposed management algorithm. J. Neurosurg. 2011; 114(1): 53–61. PubMed Abstract | Publisher Full Text\n\nXu F, et al.: The surgical management of a penetrating orbitocranial injury with a Bakelite foreign body reaching the brain stem. Brain Inj. 2013; 27(7–8): 951–956. PubMed Abstract | Publisher Full Text\n\nBorkar SA, et al.: Transorbital penetrating cerebral injury caused by a wooden stick: Surgical nuances for removal of a foreign body lodged in cavernous sinus. Childs Nerv. Syst. 2014; 30(8): 1441–1444. PubMed Abstract | Publisher Full Text\n\nMzimbiri JM, et al.: Orbitocranial Low-Velocity Penetrating Injury: A Personal Experience, Case Series, Review of the literature, and Proposed Management Plan. World Neurosurg. 2016; 87: 26–34. PubMed Abstract | Publisher Full Text\n\nSun G, et al.: Management Strategy of a Transorbital Penetrating Pontine Injury by a Wooden Chopstick. World Neurosurg. 2016; 95: 622.e7–622.e15. Publisher Full Text\n\nTabibkhooei A, Aslaninia A, Anousha K: Childhood Transorbital Skull Base Penetrating Injury: Report of 2 Cases and Review of Literature. World Neurosurg. 2019; 131: 213–216. PubMed Abstract | Publisher Full Text\n\nApriawan T, Bajamal AH, Hermawan Y, et al.: Three-dimensional (3D)-printed model reconstruction in pre-operative planning for wooden penetrating brain injury. Bioprinting. Elsevier B.V. 2021; 24(April): e00168. Publisher Full Text\n\nIbrahim M, et al.: Characterization of the foreign body response to common surgical biomaterials in a murine model. Eur. J. Plast. Surg. 2017; 40(5): 383–392. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNichols SP, et al.: The effect of nitric oxide surface flux on the foreign body response to subcutaneous implants. Biomaterials. 2012; 33(27): 6305–6312. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnderson JM, Rodriguez A, Chang DT: Foreign body reaction to biomaterials. Semin. Immunol. 2008; 20(2): 86–100. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "150802",
"date": "30 Sep 2022",
"name": "Mamoru Murakami",
"expertise": [
"Reviewer Expertise neurosurgery"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments to the author\nTitle: Transorbital approach for the management of an orbito-temporal penetrating brain injury (skull base region) secondary to wooden spikes. The authors describe a very rare case of penetrating injury, treated well via transorbital approach. The article is well written. They provide suggestions about the surgical approach and the timing of surgery, which are important in clinical practice.\nTitle and abstract: The title is appropriate for the content of the article. The abstract is concise and accurately summarises the essential information of the paper, although it would be better if authors included the comment about the timing of the surgery in conclusion.\nCase report: The clinical case presentation is well written but some minor points that should be clarified:\nThere is no comment about a conventional angiography. The wooden spike penetrated near the cavernous sinus. In case of suspicion for the injury of internal carotid artery, there are opinions that digital subtraction angiogram (DSA) should be performed to evaluate the lesion which 3DCTA could not clearly demonstrate, such as arterio-venous fistula (AVF). If you did not perform DSA in this case, could you explain that reason?\n\nThe timing of the second surgery is very important. If the foreign body is wooden, serious infection is often problematic, since the porous nature of wood is a strong growth medium for microorganisms. During waiting for 14 days to the second surgery, there might be possibility of exacerbation of epidural or subdural abscess. Some neurosurgeons might insist the early second-surgery to prevent the serious infections. In case of penetrating brain injury of wooden spikes, do you consistently recommend waiting until 14 days, which the wooden spikes form the fibrous capsule?\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? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "156737",
"date": "12 Dec 2022",
"name": "Chi Hoon Choi",
"expertise": [
"Reviewer Expertise Neroradiology & Neurointervention"
],
"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 describe a very rare case and its transorbital approach treatment. This article is important in clinical practice showing the diagnostic images and surgical approach.\n\nStrength: A very rare case Weakness: It seems necessary to summarize in order according to the flow of time rather than an additional explanation.\nTitle: - Abstract: - Background and importance: -\nClinical presentation/ Surgical procedure/ Postoperative FU: Combining the table and figure 3 would be better.\nDiscussion:\n\nI would like to divide the paragraphs and categorize them into subheadings.\n\nFigure 5: It would be helpful to describe the details of the preoperative plan by 3d printing (the specifications of the printer & ink and the simple usage environment).\n\nFigure 6: It is thought to be an inadequate picture to convey the author's intention. It can be omitted and would be better to present pathological pictures of the foreign body or clinical data of patients.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1283
|
https://f1000research.com/articles/10-1282/v1
|
15 Dec 21
|
{
"type": "Case Report",
"title": "Case Report: Right paraduodenal hernia – a unique case of rare internal hernia presenting as acute small bowel obstruction",
"authors": [
"Brikha Raj Joshi",
"Swotantra Gautam",
"Saroj Adhikari Yadav",
"Rakesh Kumar Gupta",
"Brikha Raj Joshi",
"Saroj Adhikari Yadav",
"Rakesh Kumar Gupta"
],
"abstract": "Paraduodenal hernia, a rare internal hernia, is an uncommon cause of small bowel obstruction. We present a case report of a 45-year-old male presenting to the emergency department with complaints suggestive of small bowel obstruction. Abdominal plain X-ray was also suggestive of small bowel obstruction. Emergency laparotomy showed intraoperative findings of right sided paraduodenal hernia with dilated small bowel. Postoperative hospital stay was uneventful and the patient was doing well during 24 months of follow up with no active complaints. Paraduodenal hernia should be considered as part of the differential diagnosis of small bowel obstruction in patients who have repeated attacks and no prior history of abdominal surgery. Surgeons need to have an astute clinical acumen in diagnosing internal hernias to avoid repercussions and fatal events.",
"keywords": [
"internal hernia",
"paraduodenal hernia",
"small bowel obstruction."
],
"content": "Introduction\n\nInternal hernia is an abnormal protrusion of abdominal viscera through a defect, which may be congenital or acquired, within the peritoneum or mesentery.1 Internal hernias cause 0.6 to 6.0 percent of small bowel obstructions.2 Types of internal hernia (in decreasing frequency) include paraduodenal, pericecal, Winslow foramen, transmesenteric and transmesocolic, pelvic, intersigmoid, retroanastomotic, and transomental hernia.1\n\nParaduodenal hernia is a rare congenital abnormality caused by a malrotation of the midgut. It is the most common type of internal herniation (53%) with left-sided dominance (left to right ratio is 3:1).3 Paraduodenal hernia occurs when the small intestine becomes trapped beneath the colon because of anomalous rotation of the mesentery of the developing colon in utero. The duodenum and small intestine become trapped in a sac lined by peritoneum, behind the mesentery of the colon, either to the left or to the right of the midline.4 Treatment of paraduodenal hernia is laparotomy or laparoscopy with reduction of the herniated loops and closure of the hernial orifice.5 We present a case of right paraduodenal hernia presenting in an emergency department with symptoms consistent with acute small bowel obstruction (SBO). Subsequently, supine and erect abdomen x-ray was suggestive of small bowel obstruction at the level of the ileum. The patient underwent open surgery, paraduodenal hernia was diagnosed and entrapped intestinal loops were reduced. The patient tolerated the procedure well without complications. The treatment of internal hernias needs to be prompt as the delay may lead to ominous outcome.\n\n\nCase report\n\nA 45-year-old male presented in the emergency department of B P Koirala Institute of Health Sciences, Dharan, Nepal (a tertiary care hospital in Eastern Nepal) with complaints of non-radiating dull pain in the central abdomen, moderate to severe in intensity with mild abdominal distension and not passing stool and flatus for three days’ duration. He did not receive any treatment for the condition prior presenting to emergency department. He also gave a history of on and off epigastric pain for five years that would otherwise subside after getting some over the counter analgesics (Paracetamol) and proton pump inhibitors (Pantoprazole). The patient did not have a past history of abdominal trauma or surgical intervention. The patient was non-diabetic, non-alcoholic and non-vegetarian. The psychosocial, medical and family history were not significant.\n\nOn physical examination, his pulse rate was 100 beats/minute (Normal, 60-100), respiratory rate was 18 cycles/minute (Normal, 14-20), temperature was 98°F, and blood pressure was 100/60 mmHg (Normal, <120/80). An abdominal examination showed distended abdomen with mild tenderness and peritonism without any sign of free fluid or free air in the peritoneal cavity and absent bowel sounds. Groin examination and digital rectum examination were normal.\n\nBlood investigation was done and all routine parameters were within normal limits (total leukocyte count (TLC) (8,0000, differential count (DC) (Neutrophil 60, Lymphocyte 28, Monocytes 5, Eosinophils 1, Basophils 0), random blood sugar (RBS) (115 mg/dl), urea (20 mg/dl), creatinine (0.8 mg/dl), sodium (138 mEq/L), potassium (4.1 mEq/L)). During radiological investigation, a plain X-ray of abdomen was done (supine and erect) and it was suggestive of small bowel obstruction at the level of the ileum. A computed tomography (CT) scan with contrast was not available in the emergency room so it was not done.\n\nOn the basis of history, clinical examination and investigation, exploratory laparotomy was planned for the patient. The patient was placed in supine position, general anaesthesia was given. Abdominal cavity was entered through a mid-line incision. Intraoperative findings revealed a 10 × 6 cm2 defect in the right paraduodenal area and the whole of the small intestine was herniating through the defect (Figure 1). The small bowel was reduced and the defect was repaired with silk 2/0 round body suture in an interrupted fashion (Figures 2 and 3). The rest of the abdominal findings were normal.\n\nThe patient was admitted to the surgical ward and their post-operative course was uneventful. Post-operative analgesic (Tramadol), anti-emetic (Ondansetron) and venous thromboembolism prophylaxis were provided. The patient was discharged on the 6th post-operative day. He was followed every month for couple of months and then 6 monthly. Routine investigations deemed necessary were carried out and no major diagnostic test was needed. He has been fit and healthy for 24 months of follow up with no active complaints.\n\n\nDiscussion\n\nParaduodenal hernia, also referred to as internal, congenital, retroperitoneal, or meso-colonic hernia, was first described at autopsy by Neubauer in 1786.6 Subsequently, Treitz (in 1987) provided a precise scientific description of the condition and considered it as a retroperitoneal protusion of abdominal viscera. Right paraduodenal hernias protrude into the ascending mesocolon, involving the fossa of Waldeyer, behind the superior mesenteric artery and inferior to the third portion of the duodenum.6 In 1889, the classification of hernias into the distinct left and right types was made by Jonnesco.7\n\nParaduodenal hernia may present at any age, but is usually observed between the 4th and 6th decade of life.8 It is more common in men than women, with a ratio of 3:1,2 and is more frequent on the left than right, with a ratio of 3:1.4 Fifty percent of paraduodenal hernias cause obstruction; the remainder are diagnosed incidentally at exploratory laparotomy or at necropsy.2,8\n\nThe rare prevalence and the variable symptoms make the clinical diagnosis of paraduodenal hernia a diagnostic challenge. The clinical presentation is entirely nonspecific. It remains completely asymptomatic or found accidentally during surgery or post-mortem as an acute bowel obstruction observed in around 50% of cases with the risk of gangrene and puncture.9,10 Such a myriad of clinical features often leads physicians to misdiagnose/misinterpret paraduodenal hernia as biliary disease or peptic ulcer resulting in delay in diagnosis and management and also patients receiving unnecessary therapeutic interventions only to discover obstructive and ischemic complications later.\n\nAs the lifetime risk of incarceration or strangulation is as high as 50% with 20%-50% mortality risk, surgical treatment of paraduodenal hernia is of paramount importance once diagnosed. Also the future risk of SBO is high, paraduodenal hernia detected incidentally should be repaired in same settings.11 In the present case, the diagnosis of right paraduodenal hernia was made intraoperatively as additional investigations such as CT scan with contrast was not available in the emergency room and thus not performed after the diagnosis of acute small bowel obstruction was made in emergency ward. In the present case, the defect was repaired using silk 2-0 round body sutures. Some authors have tried prosthesis placement, especially when the defects are larger.12,13 As per the literature, complete removal of sac is not advised due to potential massive blood loss from injury of nearby superior mesenteric artery and its branches.14\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 was obtained from the patient for the publication of the case report and any associated images.",
"appendix": "References\n\nMartin LC, Merkle EM, Thompson WM: Review of internal hernias: radiographic and clinical findings. Am. J. Roentgenol. 2006; 186(3): 703–717. PubMed Abstract | Publisher Full Text\n\nNewsom BD, Kukora JS: Congenital and acquired internal hernias: unusual causes of small bowel obstruction. Am. J. Surg. 1986; 152(3): 279–285. PubMed Abstract | Publisher Full Text\n\nDayananda L, Sreekumar KP, Moorthy S, et al.: Para duodenal hernias-a pictorial essay. Indian J. Radiol. Imaging 2006; 16(4): 469. Publisher Full Text\n\nBartlett MK, Wang CA, Williams WH: The surgical management of paraduodenal hernia. Ann. Surg. 1968; 168(2): 249–254. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrehm V, Smithuis R, Doornebosch PG: A left paraduodenal hernia causing acute bowel obstruction: a case report. Acta Chir. Belg. 2006; 106(4): 436–437. PubMed Abstract | Publisher Full Text\n\nFitzgibbons RJ, Greenburg AG, Nyhus LM: Nyhus and Condon's hernia. Lippincott Williams & Wilkins; 2002.\n\nJonnesco T: Anatomie topographique du duodenum et hernies duodenales. Progrès médical; 1889.\n\nBrigham RA, Fallon WF, Saunders JR, et al.: Paraduodenal hernia: diagnosis and surgical management. Surgery. 1984; 96(3): 498–502. PubMed Abstract\n\nBrunner WC, Sierra R, Dunne JB, et al.: Incidental paraduodenal hernia found during laparoscopic colectomy. Hernia. 2004; 8(3): 268–270. PubMed Abstract | Publisher Full Text\n\nKim JC, Kim MD, Jeong BG, et al.: CT findings of right paraduodenal hernia presenting as acute small bowel obstruction. J. Korean Rodiol. Soc. 2001; 44(1): 85–88. Publisher Full Text\n\nTong RS, Sengupta S, Tjandra JJ: Left paraduodenal hernia: case report and review of the literature. ANZ J. Surg. 2002; 72(1): 69–71. Publisher Full Text\n\nPalanivelu C, Rangarajan M, Jategaonkar PA, et al.: Laparoscopic management of paraduodenal hernias: mesh and mesh-less repairs. A report of four cases. Hernia. 2008; 12(6): 649–653. PubMed Abstract | Publisher Full Text\n\nAntedomenico E, Singh NN, Zagorski SM, et al.: Laparoscopic repair of a right paraduodenal hernia. Surg. Endosc. Other Interv. Tech. 2004; 18(1): 165–166. Publisher Full Text\n\nManfredelli S, Andrea Z, Stefano P, et al.: Rare small bowel obstruction: right paraduodenal hernia. Case report. Int. J. Surg. Case Rep. 2013; 4(4): 412–415. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "115433",
"date": "17 Jan 2022",
"name": "Yasith Mathangasinghe",
"expertise": [
"Reviewer Expertise Clinical Anatomy"
],
"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 Joshi et al., 2021 reports a case of right paraduodenal hernia presenting as acute small intestinal obstruction. This case is of interest to clinicians and overall the report is written in a clear and concise manner.\nTitle: Paraduodenal hernia is the most common type of internal hernia. Therefore, I suggest removing the term \"rare\" in the title. Suggested title: A case of right paraduodenal hernia presenting as acute small bowel obstruction.\nAbstract: Please briefly mention the surgical procedure. Eg: \"Entrapped small bowel loop was reduced and the defect was repaired\".\nIntroduction: The last few sentences of the introduction are a repetition of the case presentation. Suggest removing them from the introduction.\nCase presentation: Please state if the patient complained of vomiting.\nDiscussion: This could have been improved by incorporating the embryological basis of the paraduodenal hernia.\nReferences: Most references are outdated. Please refer to the latest literature. Eg: Shadhu et al., 2018\n\nFigures: Please elaborate the figure legends further. Add an arrow in Figure 2 to indicate the hernial defect.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "264371",
"date": "23 May 2024",
"name": "Noor Khairiah A Karim",
"expertise": [
"Reviewer Expertise General radiology and cardiac imaging"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author included pertinent available literature surrounding the clinical scenario. A few minor revisions are required as below:\n1. In the Abstract section, after mentioning the intraoperative findings, please include the operative procedure performed on the patient i.e. the small bowel was reduced and the defect was repaired.\n\n2. It was concluded in the Abstract section that a paraduodenal hernia should be considered as part of the differential diagnosis of small bowel obstruction in patients who have repeated attacks. Please mention that the patient had recurrent symptoms for the past 5 years in this section.\n\n3. In the Introduction section, please abbreviate the term small bowel obstruction (SBO) for first-time use in the manuscript (Para 1 Line 2) and please use the abbreviated term 'SBO' throughout the manuscript. 4. Please be consistent in using the term 'x-ray', either use a capital X (X-ray) or a smaller x (x-ray) throughout the manuscript. 5. Please be consistent in using the term 'silk 2/0', either use 2/0 (Case Report section, Para 4 Line 4) or 2-0 (Discussion section, Para 4 Line 6). 6. It would be nice to add in more latest journals (published within the last 5-10 years) as references.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1282
|
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